The study compared wild-type Mertk+/+ mice with MerTK-deficient Mertk–/– littermate controls on a C57BL/6 background. Dexamethasone was administered intraperitoneally at 2.5 mg/kg, with the dose adjusted for body weight, on days 2, 4 and 6 after infection. Researchers examined blood, spleen and liver by flow cytometry and quantified viral titres in the spleen, liver, kidney, lung and lymph nodes with a focus-forming assay. Analyses included total CD8+ T cells, LCMV GP33 tetramer-specific CD8+ T cells and markers associated with activation, differentiation and survival, including KLRG1, CD44, CD62L, CD127 and PD-1. This design allowed the investigators to compare the effect of dexamethasone in animals with and without functional MerTK under the same infection and treatment conditions.

Dexamethasone caused a pronounced loss of total CD8+ T cells in wild-type mice. The percentage of these cells declined in blood, spleen and liver, and the absolute splenic CD8+ T-cell count was substantially reduced. MerTK deficiency largely abolished this effect: Mertk–/– animals retained higher CD8+ T-cell levels under both treatment conditions. Estimation-plot comparisons showed mean genotype differences, calculated as Mertk–/– minus Mertk+/+, of −17.30 in blood, −23.78 in spleen and −17.73 in liver, with 95% confidence intervals entirely below zero; the source did not specify the measurement units for these values. These observations associate the loss of MerTK with resistance to dexamethasone-induced depletion of CD8+ T cells, although the experiment does not establish whether the cells were eliminated, redistributed or both.

The effect was also evident in CD8+ T cells detected with an MHC class I tetramer corresponding to the LCMV GP33 epitope. Dexamethasone reduced both the percentage and absolute number of GP33-specific CD8+ T cells in wild-type mice compared with saline-treated controls. By contrast, Mertk–/– mice maintained stronger LCMV-specific responses under both interventions and were largely resistant to the steroid-associated decline. Longitudinal blood measurements showed that virus-specific CD8+ T-cell percentages remained lower at the examined time points in dexamethasone-treated wild-type animals, whereas MerTK-deficient animals consistently had higher responses. The evidence therefore indicates that the suppression of both broad and virus-specific CD8+ T-cell populations depends largely on MerTK in this experimental setting.

Surface-marker analysis showed that dexamethasone also altered the differentiation state of wild-type CD8+ T cells. It reduced KLRG1, CD44 and CD127 expression, patterns consistent with diminished effector-like differentiation, activation and memory potential, while increasing CD62L, a marker associated with naïve or central-memory-like cells. MerTK-deficient mice displayed a more effector-like profile, with higher KLRG1, CD44 and CD127 and lower CD62L, and these features were relatively insensitive to dexamethasone. The investigators interpreted the combined pattern in treated wild-type mice as a shift away from effective antiviral differentiation. Because the study relied on marker phenotypes rather than direct measurements of every cytotoxic function, the results establish a change in the measured cellular state rather than demonstrating a complete loss of killing capacity.

Dexamethasone-treated wild-type mice also showed a sharp increase in IL-10 production by macrophages and dendritic cells, together with higher PD-1 expression on LCMV-specific and total CD8+ T cells. Both responses were substantially lower in Mertk–/– animals regardless of treatment. The timing and composition of the results are consistent with an inhibitory circuit in which dexamethasone reinforces MerTK-associated tolerogenic programming, increases IL-10-associated restraint and elevates PD-1, thereby weakening effective CD8+ T-cell responses. However, the study did not directly test the causal links among MerTK signalling, IL-10, PD-1 and T-cell dysfunction. Nor did it directly measure apoptotic-cell clearance, the availability of MerTK ligands GAS6 or PROS1, antigen presentation or the activity of other candidate regulatory pathways.

The immune changes coincided with worse infection outcomes. Dexamethasone dramatically accelerated viral replication in wild-type mice and produced widespread dissemination across the organs examined. The same treatment had a reduced effect in Mertk–/– animals, which maintained better viral control. This comparison supports a MerTK-dependent contribution to the steroid-associated increase in viral burden, rather than showing that dexamethasone invariably suppresses antiviral defence regardless of host genotype. The findings are consistent with the authors’ model in which MerTK serves as a link between dexamethasone exposure and impaired immune restraint during persistent infection. They do not imply that all glucocorticoids have identical effects or that the same mechanism governs every viral infection.

The authors propose several explanations for how MerTK might amplify the response to dexamethasone. Glucocorticoids can promote apoptosis, and increased exposure of phosphatidylserine on apoptotic cells could support MerTK-dependent efferocytosis and immunoregulatory signalling. Infection may also create phosphatidylserine-bearing extracellular vesicles or dysfunctional CD8+ T cells that could engage the pathway. These are mechanistic proposals rather than findings directly demonstrated in the experiment. Previous work cited by the authors found that dexamethasone can induce MerTK expression and phosphorylation in monocyte-derived dendritic cells, alter their maturation and enhance efferocytosis, while MerTK inhibition can reverse selected effects. The present study builds on that evidence by connecting the steroid–MerTK axis to antigen-specific CD8+ T-cell suppression and chronic LCMV control in vivo.

Several limitations constrain the conclusions. The downstream signalling connecting MerTK to IL-10 production and PD-1 upregulation was not directly interrogated, and the researchers performed no transcriptomic or proteomic profiling to map the wider inhibitory networks. Efferocytosis, apoptotic-cell burden, antigen presentation, GAS6 and PROS1 availability, TGF-β, SOCS proteins, regulatory B cells and Tregs were not directly examined. The use of constitutively MerTK-deficient mice also leaves open developmental compensation as an alternative explanation for their stronger immune responses. Most importantly, the research was conducted in a single mouse model of chronic viral infection, and its relevance to other persistent infections or to human treatment remains untested. Pharmacological inhibition of MerTK, conditional genetic models and systems-level immune profiling will be needed to establish more precisely how the pathway operates and whether it can be targeted without unacceptable autoimmune consequences.

Within these boundaries, the mouse experiment provides a mechanistic explanation for how dexamethasone can intensify chronic viral infection under some conditions. It shows that MerTK is necessary for much of the observed loss of total and LCMV-specific CD8+ T cells, the shift toward a less differentiated phenotype, the increase in IL-10 and PD-1 and the rise in viral burden. The study does not show that dexamethasone is inappropriate in every viral illness or that MerTK inhibition is ready for clinical use. Rather, it identifies a pathway that may connect glucocorticoid treatment to weakened antiviral control and provides a basis for testing whether blocking MerTK could preserve antiviral immunity while retaining some anti-inflammatory effects. Such an intervention remains a research objective requiring pharmacological, safety and human-translation studies.

Subject of Research: MerTK-dependent dexamethasone suppression of antiviral CD8+ T-cell immunity during chronic LCMV infection in mice

Article Title: MerTK mediates dexamethasone-induced suppression of antiviral CD8+ T cell immunity and exacerbates chronic LCMV infection

Article References: Adomati, T., Hamdan, T. A., Seliger, B., Duhan, V., Akite, J. E., Ariaka, H., Bhat, H., Ali, M., & Cham, L. B. (2026). MerTK mediates dexamethasone-induced suppression of antiviral CD8+ T cell immunity and exacerbates chronic LCMV infection. Frontiers in Cellular and Infection Microbiology, 16, 1961552. https://doi.org/10.3389/fcimb.2026.1961552

Image Credits: AI Generated

DOI: 10.3389/fcimb.2026.1961552

Keywords: MerTK, dexamethasone, LCMV, chronic viral infection, CD8+ T cells, antiviral immunity, IL-10, PD-1, glucocorticoids, viral dissemination, mediates, dexamethasone-induced

The experiment involved 18 specific-pathogen-free male C57BL/6 mice aged 2–3 weeks. After a week of acclimatization, the mice were assigned to three groups of six: an untreated control group, an antibiotic group and a fecal microbiota transplantation group. The latter two groups received a broad-spectrum oral antibiotic cocktail containing ampicillin, gentamicin and vancomycin twice daily for eight consecutive days. Antibiotic-only mice then received sterile phosphate-buffered saline by gavage for four days, while transplantation recipients received a fecal microbiota suspension by the same route once daily for that period.

The donor suspension was prepared from pooled feces collected from five healthy, untreated 8-week-old adult C57BL/6J mice. It was administered at 0.1 mL per mouse and used within two hours of preparation. The investigators did not sequence the donor inoculum, so the analyses could not directly establish the origin or engraftment rate of specific donor strains. They also did not include a comparison group receiving age-matched juvenile donor material.

Microbial composition was assessed by sequencing the V3–V4 regions of the 16S rRNA gene, with six mice per group. Antibiotic exposure sharply reduced the Chao1 richness and Shannon diversity indices compared with controls, with P values below 0.001 for both measures. After transplantation, the Shannon index recovered to a level that did not differ significantly from the control group, while the Chao1 index showed a partial, statistically significant improvement over the antibiotic group. Principal coordinate analysis based on unweighted UniFrac distance showed distinct community structures among the three groups, with an Adonis R-squared value of 0.582 and P=0.001.

The transplanted microbiota was not simply a return to the pre-antibiotic juvenile composition. Antibiotic-treated mice showed marked depletion of taxa including Muribaculaceae and Lachnospiraceae_NK4A136_group and a substantial relative expansion of Bacteroides. Fecal microbiota transplantation was associated with reduced Bacteroides abundance and recovery of Muribaculaceae to levels not significantly different from controls. It also increased the relative abundance of low-abundance taxa and produced biomarker profiles that included Parabacteroides, Lachnoclostridium, Tannerellaceae and members of Desulfobacterota. The investigators characterized these findings as a distinct community state, although they could not confirm that the detected taxa originated from the adult donor because the inoculum itself was not sequenced.

Colonic tissue was collected on day 13 from three randomly selected mice per group for molecular analyses. Quantitative reverse-transcription polymerase chain reaction showed that antibiotics increased colonic transcript levels of IL-10, IL-17 and IL-22 relative to controls, with P values of 0.01 or lower. Transplantation was associated with lower IL-17 and IL-22 expression than antibiotic treatment alone, with P=0.036 and P=0.024, respectively. IL-10 expression in the transplantation group did not differ significantly from the antibiotic group, at P=0.068, and remained higher than in controls, at P=0.014.

Western blot analysis provided a partial measure of changes in the TLR4/MyD88 signaling axis. Antibiotic-treated mice had higher colonic TLR4 and MyD88 protein abundance than controls, with P values below 0.001. After transplantation, TLR4 abundance was significantly lower than in the antibiotic group, at P=0.011. MyD88 showed a downward trend but did not differ significantly from the antibiotic-only group. These measurements therefore associated fecal microbiota transplantation with attenuation of TLR4 expression and IL-17 and IL-22 transcription, rather than demonstrating a complete normalization of the pathway or the immune state.

Several limitations constrain the findings. The molecular endpoints were based on three mice per group, limiting the study’s ability to detect smaller differences in immune responses. Quantitative body-weight and food-intake data were not systematically recorded, and intestinal barrier function and tissue architecture were not assessed. The study also lacked luminal lipopolysaccharide and short-chain fatty acid measurements, direct sequencing of the pooled donor material, and an age-matched donor comparison. The findings consequently establish changes in mouse gut microbial composition and selected colonic immune markers over a short follow-up; they do not demonstrate a human clinical benefit, long-term stability of the transplanted community or restoration of mucosal homeostasis.

Overall, the mouse experiment indicates that a four-day course of adult-sourced fecal microbiota transplantation following early-life antibiotic exposure was associated with a partly restored microbial diversity index, suppression of antibiotic-associated Bacteroides expansion, a distinct taxonomic profile and lower selected intestinal immune markers. The authors said the results warrant further investigation of donor-age effects on microbial and mucosal immune recovery, while the absence of donor sequencing, a juvenile-donor comparator, functional barrier assays and a larger molecular sample limits stronger mechanistic conclusions.

Subject of Research: Effects of adult-sourced fecal microbiota transplantation on antibiotic-disrupted gut microbiota and colonic immune markers in juvenile mice

Article Title: Adult-sourced fecal microbiota transplantation ameliorates early-life antibiotic-induced intestinal immune stress in juvenile mice associated with the modulation of the TLR4/MyD88 signaling pathway

Article References: Qian, X., Shen, Y., Luo, X., Zhang, S., Wang, L., He, H., & Wang, B. (2026). Adult-sourced fecal microbiota transplantation ameliorates early-life antibiotic-induced intestinal immune stress in juvenile mice associated with the modulation of the TLR4/MyD88 signaling pathway. PLOS One, 21(10), e0359634. https://doi.org/10.1371/journal.pone.0359634

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0359634

Keywords: fecal microbiota transplantation, early-life antibiotics, juvenile mice, gut microbiota, TLR4, MyD88, IL-17, IL-22, IL-10, 16S rRNA sequencing, Adult-sourced, fecal

The researchers recruited 60 patients with SLE and thrombocytopenia, 40 patients with SLE without thrombocytopenia and 40 healthy controls, then collected blood samples from the three groups. They measured PVT1, miR-181a, FOXP3 and RORγt gene expression using reverse-transcription polymerase chain reaction. Serum concentrations of IL-23, IL-10, lipocalin2 and matrix metalloproteinase 9 (MMP9) were measured with enzyme-linked immunosorbent assays.

Among patients with thrombocytopenic SLE, serum IL-23, lipocalin2 and MMP9 concentrations were higher and IL-10 concentrations were lower than in the non-thrombocytopenic SLE and healthy control groups. The abstract also reports increased miR-181a and RORγt expression, decreased PVT1 and FOXP3 expression, a higher IL-23 level and a lower IL-10 level among thrombocytopenic SLE patients with positive antiphospholipid antibodies. It does not identify the comparison group for that subgroup result or provide complete numerical data.

The authors interpret PVT1/miR-181a as a possible upstream regulator of the RORγt/FOXP3 balance and its associated IL-23 and IL-10 markers, linking these patterns to the possible pathogenesis of SLE-associated thrombocytopenia. The findings are observational associations and do not establish that the measured RNA or cytokine patterns cause thrombocytopenia, antiphospholipid antibodies, bleeding or thrombosis. The abstract reports no effect sizes, confidence intervals, longitudinal outcomes or diagnostic-performance measures. Because only the abstract was available, the full methods, statistical analyses and results could not be assessed; the results identify candidate markers for further investigation but do not establish diagnostic accuracy, predict future complications or demonstrate a clinical benefit from targeting these pathways.

Subject of Research: Molecular marker differences in systemic lupus erythematosus-associated thrombocytopenia

Article Title: Unravelling the role of the non-coding RNAs PVT1/miR-181a in orchestrating IL-23/RORγt and FOXP3/IL-10 axes in thrombocytopenia associated with systemic lupus erythematosus: insights into the clinical paradox of antiphospholipid syndrome

Article References: Abd-Elmawla, M. A., Shaker, O. G., Mamdouh, M., Zekry, S. S., Ibrahim, S. G., Hegazy, G. A., & Ayeldeen, G. (2026). Unravelling the role of the non-coding RNAs PVT1/miR-181a in orchestrating IL-23/RORγt and FOXP3/IL-10 axes in thrombocytopenia associated with systemic lupus erythematosus: insights into the clinical paradox of antiphospholipid syndrome. Molecular Biology Reports, 53(1), Article 1576. https://doi.org/10.1007/s11033-026-12551-x

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12551-x

Keywords: systemic lupus erythematosus, thrombocytopenia, PVT1, miR-181a, RORγt, FOXP3, IL-23, IL-10, antiphospholipid antibodies, biomarkers, Unravelling, role

The investigation began with a systematic characterization of the fecal microbiome in mice with surgically induced endometriosis. Using 16S rDNA sequencing of the V3–V4 hypervariable region on an Illumina NovaSeq 6000 platform, the researchers profiled the gut microbiota of endometriosis and control mice during diestrus at day 42 post-model establishment. After quality filtering, 700 amplicon sequence variants were shared between groups, with 583 unique to controls and 536 unique to endometriosis mice. Alpha-diversity indices, including Chao1, Shannon, Pielou’s evenness, and Good’s coverage, did not differ significantly between groups, suggesting that overall species richness and evenness remained intact. However, beta-diversity analysis revealed clear structural separation between groups, confirmed by unweighted UniFrac-based principal coordinates analysis, hierarchical clustering, and analysis of similarities. At the phylum level, endometriosis mice showed reduced Firmicutes abundance and increased Bacteroidota, with a significantly altered Firmicutes-to-Bacteroidota ratio compared to controls. Linear discriminant analysis effect size analysis further delineated taxon-level compositional differences, and indicator species analysis nominated g_Ruminococcus, g_Coprococcus, g_Muribaculum, and g_Duncaniella as candidate endometriosis-associated biomarkers. Functional prediction using PICRUSt2 against the KEGG database identified enrichment of sphingolipid biosynthesis and metabolism pathways in endometriosis mice, hinting that lipid metabolism might be a key functional consequence of the dysbiosis.

To translate these compositional shifts into metabolic consequences, the team performed non-targeted liquid chromatography-mass spectrometry metabolomics on peritoneal lavage fluid from endometriosis and control mice. Partial least-squares discriminant analysis revealed clear separation between the metabolic profiles of the two groups, and a 200-permutation test confirmed model robustness without overfitting. Applying thresholds of fold change greater than or equal to 1.2 or less than or equal to 1/1.2, p less than 0.05, and variable importance in projection greater than or equal to 1, the researchers identified 26 upregulated and 2 downregulated metabolites in the endometriosis group. Among these, LysoPC(16:0) exhibited one of the largest fold-changes, highlighted in a heatmap of the top 28 differential metabolites. KEGG pathway enrichment of the full differential metabolite set identified glycerophospholipid metabolism, choline metabolism, linoleic acid metabolism, and unsaturated fatty acid biosynthesis among the top 20 enriched pathways, placing LysoPC(16:0) within a broader lipid metabolic reprogramming of the peritoneal cavity. Spearman’s correlation analysis between significantly altered genera and differential metabolites revealed that multiple genera, including g_Muribaculum, g_Mucispirillum, g_Ruminococcus, and g_Lactiplantibacillus, showed significant positive correlations with peritoneal LysoPC(16:0), suggesting a potential microbiota-metabolite link that demanded causal testing.

The researchers then turned to fecal microbiota transplantation to establish causality. Mice were rendered pseudo-germ-free by a seven-day antibiotic cocktail regimen containing vancomycin, ampicillin, metronidazole, and neomycin sulfate before endometriosis model establishment. Beginning on day 1 after model establishment and repeated every three days, mice were gavaged with sterile phosphate-buffered saline, fecal suspension from control mice, or fecal suspension from endometriosis mice. Peritoneal LysoPC(16:0) was significantly higher in recipients of endometriosis-donor feces than in either control group. These mice also developed heavier lesions and showed a greater proportion of CD206-positive macrophages, a canonical M2 marker, in peritoneal lavage fluid compared with control recipients. These results demonstrated that endometriosis-associated gut microbiota is sufficient to elevate peritoneal LysoPC(16:0) and promote peritoneal M2 macrophage accumulation, thereby facilitating lesion growth. The finding represents a critical advance because it moves beyond correlation to demonstrate that the altered microbiota itself carries the pro-endometriotic signal, with the lipid metabolite serving as the functional mediator between gut dysbiosis and pelvic immune remodeling.

To dissect the cellular mechanism, the team isolated bone marrow-derived macrophages from the femurs and tibias of eight-week-old C57BL/6N mice, cultured them with macrophage colony-stimulating factor for seven days, and stimulated them under multiple conditions. Flow cytometry showed that 50 micromolar LysoPC(16:0) significantly augmented IL-4-induced CD206 expression, confirming that the metabolite promotes M2 polarization in vitro. In a Transwell co-culture assay, mouse endometrial stromal cells placed in the upper chamber migrated significantly more when co-cultured with IL-4 plus LysoPC(16:0)-stimulated macrophages in the lower chamber than with either negative control or IL-4-alone conditions. Additionally, a phagocytosis assay using phycoerythrin-conjugated microspheres demonstrated that LysoPC(16:0)-treated macrophages exhibited enhanced particle uptake over two hours, consistent with prior reports that lysophosphatidylcholine promotes macrophage phagocytic activity. These in vitro findings established that LysoPC(16:0) directly reshapes macrophage phenotype and function, with downstream consequences for endometrial stromal cell migration, a pivotal step in ectopic lesion formation.

In vivo, the researchers administered daily intraperitoneal injections of LysoPC(16:0) to endometriosis mice for two weeks. Mice treated with the metabolite developed larger lesions than vehicle controls, whereas mice treated with AACOCF3, a phospholipase A2 inhibitor that suppresses endogenous LysoPC(16:0) production, showed smaller lesions and a lower proportion of peritoneal CD206-positive macrophages relative to endometriosis controls. To determine whether PPARγ signaling underlies the M2-polarizing activity of LysoPC(16:0), the team used GW9662, a selective PPARγ antagonist. In bone marrow-derived macrophages, LysoPC(16:0) significantly augmented IL-4-induced CD206-positive polarization, and this was substantially reduced by GW9662 pretreatment. In vivo, LysoPC(16:0)-t mice developed heavier lesions and showed a higher proportion of peritoneal CD206-positive macrophages than vehicle controls, and GW9662 co-administration significantly reduced both parameters. To assess whether these findings extend beyond a single genetic background, the researchers repeated the experiment in BALB/c mice using a four-group design, and the directional results were consistent with those in C57BL/6N mice across all outcome measures, confirming that the LysoPC(16:0)–PPARγ–M2 axis is not strain-specific but operates across genetically distinct backgrounds.

A key mechanistic advance of the study is the identification of IL-10 as the downstream effector through which LysoPC(16:0)-polarized M2 macrophages promote lesion progression. Reverse transcription quantitative polymerase chain reaction demonstrated that LysoPC(16:0) significantly upregulated Il10 messenger RNA in IL-4-primed macrophages in a PPARγ-dependent manner, placing IL-10 transcription within the LysoPC(16:0)–PPARγ cascade. The functional importance of IL-10 was confirmed in vivo: neutralizing IL-10 in LysoPC(16:0)-supplemented endometriosis mice with an anti-mouse IL-10 neutralizing antibody significantly reduced lesion weight compared with isotype controls. To formally establish that peritoneal macrophages are causally required rather than incidental bystanders, the researchers co-administered clodronate liposomes to deplete macrophages in LysoPC(16:0)-treated endometriosis mice. At day 14, clodronate-treated mice showed markedly fewer F4/80-positive cells in peritoneal lavage fluid and significantly lower lesion weights than empty liposome controls, despite equivalent LysoPC(16:0) exposure. Macrophage depletion therefore abolished the pro-endometriotic effect of LysoPC(16:0), demonstrating that peritoneal macrophages are required mediators of the metabolite-driven lesion growth.

To provide preliminary cell-based evidence relevant to human endometriosis, the researchers employed two complementary human models. THP-1 monocytes were differentiated into macrophages by phorbol 12-myristate 13-acetate treatment, rested for 24 hours, and stimulated under four conditions: negative control, IL-4/IL-13, IL-4/IL-13 plus LysoPC(16:0), and IL-4/IL-13 plus LysoPC(16:0) plus GW9662. LysoPC(16:0) significantly increased the proportion of CD206-positive cells compared with IL-4/IL-13 alone, and GW9662 reversed this effect, recapitulating the PPARγ-dependent polarization observed in murine macrophages. Conditioned medium was then collected from THP-1 macrophages stimulated under six conditions, including IL-10 neutralization with an anti-human IL-10 antibody or a human IgG1 isotype control. Primary endometrial stromal cells were isolated from ectopic lesions of five patients with surgically and histologically confirmed endometriosis, aged 26 to 37 years with a median age of 33, all with rAFS stage III–IV disease. Conditioned medium from LysoPC(16:0)-stimulated macrophages promoted significantly greater stromal cell migration than conditioned medium from IL-4/IL-13-alone conditions across all five patient samples, and this enhancement was substantially reduced by GW9662 or IL-10 neutralization but not by the isotype control. The consistency of the conditioned medium effect across five independent patient specimens, each tested under all six conditions in parallel, provides preliminary evidence that the axis identified in murine models is also operative in human cells.

The researchers acknowledge several limitations that place practical bounds on these conclusions. The bacterial taxa ultimately responsible for LysoPC(16:0) production were not isolated at the species level, as several candidate genera are obligate anaerobes whose cultivation requires dedicated infrastructure. Confirming a direct strain-metabolite relationship will require single-strain gnotobiotic colonization. The link between LysoPC(16:0) and PPARγ was established pharmacologically with GW9662, consistent with earlier reports that structurally related lysophospholipids can act as PPARγ ligands, but direct biophysical evidence of binding, such as co-crystallography or surface plasmon resonance, was not obtained. Likewise, IL-10 was identified as the principal downstream effector, but transforming growth factor beta and other M2-associated cytokines were not systematically profiled, and how IL-10 signaling drives endometrial stromal cell migration, whether through JAK-STAT3, PI3K-AKT, or another route, remains to be worked out. The translational component relied on a monocyte-derived cell line and primary stromal cells from five patients, a cohort that cannot capture the clinical heterogeneity of endometriosis across disease stage, lesion subtype, or symptom severity. Despite these limitations, the findings carry potential clinical relevance that warrants further exploration. Elevated peritoneal LysoPC(16:0) and altered microbiota composition could be evaluated as candidate biomarkers for endometriosis in future clinical studies, and the phospholipase A2–LysoPC(16:0)–PPARγ–IL-10 cascade offers multiple candidate intervention points for preclinical exploration. As the work is primarily based on murine models and cell-based human systems, its findings should be interpreted as preclinical mechanistic evidence, with clinical applicability to be established in future patient studies.

Subject of Research: Intestinal microbiota-associated LysoPC(16:0) promotes endometriosis via PPARγ-mediated M2 macrophage polarization and IL-10 secretion

Article Title: Intestinal microbiota-associated LysoPC(16:0) promotes endometriosis via PPARγ-mediated M2 macrophage polarization and IL-10 secretion

Article References: Li, N., Yuan, M., Jin, X., Jiao, X., Wang, S., Zhong, Z., Guan, H., Le, X., Ren, Q., Liu, Y., Dong, X., Li, Q., Wang, M., & Wang, G. (2026). Intestinal microbiota-associated LysoPC(16:0) promotes endometriosis via PPARγ-mediated M2 macrophage polarization and IL-10 secretion. iScience, 29(11), Article 117917. https://doi.org/10.1016/j.isci.2026.117917

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117917

Keywords: Intestinal, microbiota-associated, LysoPC, promotes, endometriosis, PPAR, mediated, macrophage, polarization, IL-10, secretion, scientific research

The receptor biology underlying HLA-G function deserves closer consideration because it determines which immune cell populations are affected when HLA-G appears in infected tissue. LILRB1 and LILRB2 belong to a family of immunoglobulin-like transcripts characterized by cytoplasmic motifs that, upon ligand binding, recruit phosphatases capable of dampening activating signaling cascades. When these receptors are engaged on natural killer cells, cytotoxicity is suppressed; when engaged on dendritic cells and macrophages, antigen presentation and pro-inflammatory cytokine production are attenuated; and when engaged on T lymphocytes, proliferation and effector function are curtailed. Because these receptors are distributed across both innate and adaptive lineages, a single tolerogenic molecule can exert coordinated suppression across multiple arms of the immune response simultaneously. This breadth of action distinguishes HLA-G from more narrowly targeted evasion mechanisms, such as fungal capsules that resist phagocytosis or enzymes that degrade complement, and explains why its exploitation would be particularly advantageous for pathogens seeking long-term persistence.

The damage-response framework referenced in the review offers a useful lens for interpreting why HLA-G induction during fungal infection could produce divergent clinical outcomes. According to this framework, the same pathogen-mediated immune alteration can be beneficial, neutral, or harmful depending on the host’s baseline immune status. In an immunocompetent individual, moderate HLA-G induction might serve as a homeostatic brake that prevents collateral tissue damage during fungal clearance, allowing the infection to be resolved without excessive inflammation. In a severely immunocompromised host, however, the same HLA-G activity could tip the balance decisively toward pathogen persistence by suppressing the residual antifungal effector mechanisms that remain. This context-dependence has practical implications: therapeutic interventions aimed at blocking HLA-G signaling would need to be calibrated to the patient’s immune status, since removing a compensatory regulatory mechanism in a hyperinflammatory patient could exacerbate tissue injury even as it enhances fungal killing.

The IL-10–HLA-G feedback loop described in the review warrants additional attention because self-amplifying circuits of this kind can establish stable immunosuppressive microenvironments that are difficult to reverse. When IL-10 induces HLA-G expression, and HLA-G in turn promotes further IL-10 production, the resulting positive feedback can lock infected tissue into a tolerogenic state even after the initial inflammatory trigger has subsided. This dynamic has been documented in chronic viral infections, where sustained IL-10 and soluble HLA-G levels correlate with impaired pathogen-specific T-cell responses and difficulty achieving immune reactivation. If a similar dynamic operates during chronic fungal infections—such as those caused by Candida species colonizing mucosal surfaces or by dimorphic fungi establishing latent infection—the feedback loop could contribute to the persistence and recurrence that characterize these conditions. Disrupting this loop at either node, whether through IL-10 neutralization or HLA-G receptor blockade, represents a potential host-directed therapeutic strategy that would enhance endogenous antifungal immunity rather than targeting the fungus directly.

The role of chitin as a fungal-derived trigger for IL-10 production illustrates how specific structural components of the fungal cell wall can actively shape the immunological tone of the host response. Chitin is normally buried beneath outer layers of glucans and mannoproteins, but it becomes exposed during cell wall remodeling, budding, and damage caused by antifungal drugs. Once accessible, chitin engages pattern recognition receptors including the mannose receptor, NOD2, and Toll-like receptors, and this coordinated signaling preferentially drives IL-10 rather than pro-inflammatory cytokines. This is a striking example of fungal structural biology being repurposed for immune evasion: a molecule that serves an essential structural role in the cell wall simultaneously functions as an immunoregulatory trigger when exposed. The clinical implication is that antifungal treatment itself, by damaging cell walls and exposing chitin, might inadvertently enhance the very immunosuppressive pathways that facilitate persistence, suggesting that combination approaches pairing antifungals with immunoregulatory modulation could be more effective than either alone.

Transforming growth factor-β, the second cytokine highlighted in the review, operates through partially overlapping but mechanistically distinct pathways compared with IL-10. While IL-10 primarily suppresses antigen-presenting cell function and Th1 responses, TGF-β exerts broader effects on immune cell differentiation, promoting the generation of regulatory T cells and inhibiting the differentiation of pro-inflammatory Th17 cells that are important for mucosal antifungal defense. The convergence of IL-10 and TGF-β on HLA-G expression creates a scenario in which multiple regulatory cytokines induced during fungal infection could act synergistically to establish a tolerogenic microenvironment. This convergence is significant because it means that blocking any single cytokine pathway may be insufficient to prevent HLA-G induction; instead, combination strategies targeting multiple regulatory axes simultaneously may be required to fully restore protective antifungal immunity.

The concept of host-directed therapy, which the review identifies as a potential application of this research, represents a growing paradigm in infectious disease management. Rather than developing new antifungal compounds that target pathogen-specific molecules—a strategy constrained by the limited number of druggable fungal targets and the toxicity of many existing agents—host-directed approaches modulate the host environment to make it less permissive for pathogen survival. Blocking HLA-G signaling, neutralizing IL-10 or TGF-β, or disrupting the feedback loops that sustain immunosuppression could restore the efficacy of existing antifungal drugs by reactivating the host’s own effector mechanisms. This approach also has the advantage of being applicable across multiple fungal species, since the host pathways being targeted are shared rather than pathogen-specific.

The translational gap between the mechanistic framework proposed in this review and clinical application remains substantial. Direct evidence that HLA-G is upregulated during human fungal infections is currently limited, and the review’s argument is built largely on the convergence of well-established pathways from other infectious and inflammatory contexts. Demonstrating that HLA-G expression is measurably elevated in tissue biopsies or serum samples from patients with invasive candidiasis, aspergillosis, or other fungal diseases would be a critical first step. Subsequent studies would need to establish that this elevation correlates with clinical outcomes such as treatment failure, fungal persistence, or disease severity, and that interventions targeting the HLA-G pathway can improve outcomes in relevant models. The heterogeneity of fungal infections—with different species, anatomical sites, and host immune contexts potentially producing different HLA-G dynamics—means that the relationship will likely need to be characterized individually for each major fungal pathogen rather than assumed to be universal.

The soluble isoforms of HLA-G, particularly HLA-G5, deserve specific consideration in the context of fungal disease because they can circulate systemically and exert immunoregulatory effects at sites distant from their cellular source. If fungal infections induce soluble HLA-G release from monocytes or other cell types, this could contribute to the systemic immunosuppression observed in invasive fungal disease, potentially explaining why disseminated fungal infections are associated with broad defects in cell-mediated immunity that extend beyond the local site of infection. Measuring soluble HLA-G levels in the serum of patients with invasive mycoses could therefore serve both as a biomarker of disease severity and as a mechanistic indicator of the immunoregulatory processes driving pathogenesis.

The genetic variability of the HLA-G locus adds another dimension to this question. The HLA-G gene is polymorphic, and certain alleles are associated with higher or lower expression levels of both membrane-bound and soluble forms. If fungal pathogens do indeed exploit HLA-G-mediated tolerance, individuals carrying high-expressor alleles might be disproportionately susceptible to fungal persistence or chronic infection, while those with low-expressor variants might be relatively protected. Conversely, the same high-expressor alleles might protect against immunopathology in settings where fungal-induced inflammation is excessive. Understanding how HLA-G polymorphisms influence susceptibility to fungal disease could open new avenues for risk stratification and personalized management of patients at high risk for invasive mycoses, such as those undergoing hematopoietic stem cell transplantation or receiving prolonged immunosuppressive therapy.

The comparison between fungal and viral exploitation of HLA-G is instructive because it highlights both the plausibility of the hypothesis and the specific challenges that fungal infections present. Viruses, as intracellular pathogens, can directly manipulate host gene expression through viral proteins that interfere with transcriptional regulation, making it straightforward to envision how they might upregulate HLA-G. Fungi, as predominantly extracellular pathogens, lack this direct access to the host nucleus and must instead rely on indirect mechanisms—such as inducing host cytokines like IL-10 and TGF-β, or releasing cell wall components that trigger regulatory signaling—to create conditions permissive for HLA-G expression. This indirect route is less efficient but potentially more difficult to block, since it involves multiple host pathways rather than a single viral effector. It also means that the timing and magnitude of HLA-G induction during fungal infection would depend on the complex interplay between fungal burden, host cytokine production, and tissue microenvironmental factors, making the relationship more variable and context-dependent than in viral systems.

The broader significance of this hypothesis extends beyond fungal pathogenesis to the general question of how immune checkpoint pathways are co-opted across infectious diseases. If HLA-G serves as a convergent target for diverse pathogens—viruses, parasites, and potentially fungi—this suggests that it represents a fundamental vulnerability in host defense that pathogens have independently discovered through convergent evolution. Understanding the common principles governing this exploitation could inform therapeutic strategies that are broadly applicable across multiple infectious diseases, rather than being specific to a single pathogen. It also raises the possibility that other immune checkpoint molecules beyond HLA-G, such as programmed death ligand 1 or cytotoxic T lymphocyte-associated antigen 4, may similarly be exploited during fungal infection, creating a network of overlapping immunosuppressive mechanisms that collectively enable persistence.

Future research directions emerging from this framework include the systematic measurement of HLA-G expression in clinical specimens from patients with defined fungal infections, the use of in vitro models to test whether fungal stimuli directly or indirectly induce HLA-G in human monocytes and dendritic cells, and the development of animal models in which HLA-G signaling can be experimentally manipulated to determine its causal role in fungal persistence. Each of these approaches addresses a specific gap in the current evidence base, and together they would provide the foundation needed to translate the mechanistic hypothesis into clinically actionable insights. The intersection of fungal immunology and immune checkpoint biology remains largely uncharted territory, and the framework presented here offers a structured starting point for systematic investigation.

Subject of Research: Immunology

Article Title: Do fungal pathogens exploit HLA-G-mediated immune tolerance?

Article References: AlSaleh, A., & Farid, E. (2026). Do fungal pathogens exploit HLA-G-mediated immune tolerance?. Frontiers in Molecular Biosciences, 13, Article 1963030. https://doi.org/10.3389/fmolb.2026.1963030

Image Credits: AI Generated

DOI: 10.3389/fmolb.2026.1963030

Keywords: HLA-G, fungal infections, immune evasion, IL-10, TGF-beta, host-directed therapy, fungal, pathogens, exploit, HLA-G-mediated, immune, tolerance

The significance of this work lies in the central mystery it helps to address. Parkinson’s disease affects more than ten million people worldwide and is characterised by two intertwined processes: the progressive death of dopamine-producing neurons in a region of the brain called the substantia nigra, and the build-up of abnormal clumps of alpha-synuclein inside nerve cells. These aggregates, known as Lewy bodies and Lewy neurites at later stages, are thought to contribute to neuronal dysfunction and death. For years, therapeutic strategies have sought ways to prevent the formation of these clumps or to clear them once they appear, but the tools of the brain’s own immune system have generally been viewed with ambivalence. Microglia, when persistently activated, are known to release inflammatory signals that can damage neurons, and much of the recent literature has cast them as accomplices in neurodegeneration rather than as protectors.

The Oxford team, led by first author Dr Hung-Ju Chueh and senior author Professor George Tofaris of the Nuffield Department of Clinical Neurosciences, approached the question with a human-specific experimental system. They derived induced pluripotent stem cells, which can be reprogrammed to become almost any cell type in the body, and used them to generate both dopamine-producing neurons and microglia in the laboratory. This allowed the two cell types to be studied together in a controlled environment that reflects human biology far more closely than animal models, in which alpha-synuclein aggregation and microglial behaviour can differ substantially from the human condition. The researchers then created conditions in which alpha-synuclein aggregates formed inside the neurons, either by increasing the dosage of the alpha-synuclein gene or by exposing the cells to pre-formed alpha-synuclein fibrils that act as molecular templates, coaxing the neurons’ own protein to misfold in the same characteristic way.

What the team observed when microglia encountered these aggregate-laden neurons was striking. The immune cells did not engulf and digest entire neurons, as might be expected in a conventional phagocytic response to damaged cells. Instead, they engaged in a process called trogocytosis, from the Greek word for gnaw, in which one cell nibbles small portions of material from the membrane or cytoplasm of another. In this case, the microglia selectively removed the portions of the neuron containing the aggregated alpha-synuclein, effectively extracting the pathological protein from within the living cell. Dr Chueh emphasised the precision of this response, noting that the microglia were not simply engulfing damaged neurons but instead removing parts of the neuron containing aggregated alpha-synuclein, which suggests that at certain stages of the disease microglia help neurons dispose of potentially harmful material.

This distinction matters enormously for how the immune system is understood in neurodegeneration. Trogocytosis has been described in other contexts, particularly in the immune system’s interactions with tumour cells and in certain developmental processes, but its role in clearing intracellular protein aggregates from neurons had not been demonstrated before. The mechanism offers a way for the brain to deal with a problem that ordinary protein degradation pathways inside the neuron apparently cannot solve on their own. Aggregated alpha-synuclein is notoriously resistant to the cell’s internal disposal machinery, including the proteasome and lysosome systems, and once seeds of misfolded protein take hold they can propagate from cell to cell, spreading pathology through connected brain circuits. A mechanism by which microglia can reach into neurons and remove these seeds while preserving neuronal structure and function represents a fundamentally different kind of intervention from simply killing and replacing damaged cells.

The research went further, dissecting the molecular signals that govern this protective behaviour. The team found that the response was fine-tuned by communication between the two cell types through specific receptors: P2RY12, a receptor involved in microglial sensing and surveillance, and CD22, an inhibitory receptor that restrains immune activation. In addition, the microglia operated under what the researchers describe as a self-regulated brake, mediated by the cytokine IL-10, an anti-inflammatory signalling molecule that the cells produce themselves. This internal braking system prevents the microglia from escalating into a full inflammatory response that would damage healthy tissue, ensuring that the nibbling remains targeted and proportionate. The interplay of sensing signals, inhibitory checkpoints and self-produced anti-inflammatory feedback suggests a carefully calibrated system rather than a crude immune reaction.

Using single-cell RNA sequencing, a technique that allows researchers to read the gene expression profiles of individual cells rather than averaging across a whole population, the team identified a distinct subpopulation of activated microglia associated with this beneficial clearance response. This is an important methodological advance, because bulk analyses of microglial gene expression in diseased brains have often lumped together cells performing very different functions, some harmful and some protective. Being able to distinguish a clearance-competent microglial state opens the possibility of identifying equivalent cells in human brain tissue and, ultimately, of finding ways to expand or enhance this population therapeutically. Professor Tofaris noted that the findings highlight that the immune response in Parkinson’s disease is more nuanced than simply being beneficial or harmful, and that understanding how to enhance and monitor such beneficial microglial functions without triggering damaging inflammation could open up new avenues for developing disease-modifying treatments.

A second major discovery concerns a protein called glycoprotein non-metastatic melanoma protein B, or GPNMB, which appears to be an essential component of the protective machinery. Genetic variation at the GPNMB locus had previously been linked to Parkinson’s disease risk through genome-wide association studies, large-scale genetic surveys that compare the DNA of patients and healthy controls, but the functional role of the protein in the disease had remained unclear. The Oxford researchers found that GPNMB was upregulated in microglia exposed to neurons containing alpha-synuclein aggregates, and that the protein interacted with the pathological alpha-synuclein inside the microglia after the material had been nibbled away from the neurons. Crucially, when the team selectively reduced GPNMB expression in microglia using CRISPR interference, a genetic technique that silences specific genes without cutting the DNA, the cells became markedly less effective at clearing the aggregates, providing direct evidence that GPNMB plays an active role in the process rather than being a passive byproduct.

The human relevance of the GPNMB finding was reinforced by evidence from brain tissue. The researchers examined post-mortem tissue from the substantia nigra, the brain region most affected in Parkinson’s disease, from individuals who had died with either incidental alpha-synuclein pathology, an asymptomatic stage in which the protein aggregates are present without clinical disease, or full Parkinson’s disease. In both cases, GPNMB was increased in the microglia of this vulnerable region. This pattern suggests that the protective response is not merely an artefact of the laboratory system but occurs in the human brain, and that it may be engaged even in the earliest pathological stages, before symptoms emerge. If so, the window during which enhancing microglial clearance could slow or prevent disease progression may be wider than previously assumed, and GPNMB levels could potentially serve as a marker of this protective activity.

The broader implications of the study extend across several fronts in Parkinson’s research. First, it provides a concrete mechanism by which the immune system can be protective in neurodegeneration, countering the prevailing narrative of microglia as primarily inflammatory villains and suggesting that blanket immunosuppression might inadvertently remove a beneficial defence. Second, it identifies molecular targets, including the P2RY12 and CD22 signalling pathways, the IL-10 brake and GPNMB itself, that could be manipulated pharmacologically to strengthen the clearance response. Third, it demonstrates the power of human stem cell co-culture systems combined with single-cell profiling to reveal biology that animal models have missed. Much work remains before these findings translate into treatments: the researchers and the field will need to determine how trogocytosis is triggered in the living brain, how it changes as disease advances, and whether enhancing it in patients is safe and effective. But for a disease in which available therapies manage symptoms without slowing the underlying neurodegeneration, the image of brain immune cells carefully nibbling toxic protein out of struggling neurons offers a genuinely new and hopeful direction for disease-modifying drug development.

Subject of Research: Microglial clearance of intraneuronal alpha-synuclein aggregates in Parkinson's disease

Article Title: Brain immune cells protect neurons in Parkinson’s disease by “nibbling” harmful material

Article References: Brain immune cells protect neurons in Parkinson’s disease by “nibbling” harmful material. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: Parkinson's disease, microglia, alpha-synuclein, trogocytosis, GPNMB, neurodegeneration, dopamine neurons, iPSC models, single-cell RNA sequencing, IL-10, substantia nigra, neuroimmunology

Paraprobiotics are inactivated microbial cells or their components: bacteria that have been rendered incapable of replication but that retain structural molecules, such as cell wall fragments, surface proteins, and other immunologically active constituents. Because the cells are dead, they carry none of the risks associated with applying live microorganisms to an open wound—no chance of opportunistic infection, no uncontrolled proliferation in immunocompromised tissue, and fewer concerns about horizontal gene transfer. Yet the evidence base for probiotics suggests that many of their beneficial effects on the immune system do not require viability at all. The molecular patterns displayed by inactivated cells can still be recognized by innate immune receptors, modulating inflammatory signaling pathways in ways that may be therapeutically useful. The Iranian team set out to test whether this immunomodulatory potential could be harnessed in one of the most hostile settings in wound care: a burn wound colonized by aggressive bacteria.

The experimental design was deliberately structured to isolate the effects of the paraprobiotic treatment. The researchers created burn injuries in mice and introduced bacterial infections, then divided the animals into twelve groups of three mice each. Different groups received paraprobiotics, conventional antibiotics, or the respective control treatments, allowing direct comparison between the novel biological therapy and the established pharmaceutical approach. The model targeted second-degree burns, in which damage extends through the epidermis into part of the dermis—a depth that makes these wounds particularly vulnerable to infection and clinically significant in human patients. The work was approved by the ethics committee of the Pasteur Institute of Iran and conducted in accordance with the Declaration of Helsinki, and the study was supported by a grant from the Pasteur Institute of Iran.

What distinguishes this study from many previous evaluations of probiotic-derived therapies is the breadth of the measurements. Rather than simply tracking wound size over time, the researchers performed quantitative gene expression analysis on tissue from the wounds, profiling a panel of genes that captures both sides of the healing equation. On the inflammatory side, they measured the messenger RNA levels of three canonical proinflammatory cytokines: interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). These molecules orchestrate the early immune response to infection and injury, recruiting immune cells and amplifying antimicrobial defenses, but when their production persists unchecked they become destructive, degrading surrounding tissue and converting a contained injury into a chronic, inflamed wound bed.

On the repair side, the panel included interleukin-10 (IL-10), the body’s principal anti-inflammatory cytokine, which acts as a molecular brake on excessive immune activation; insulin-like growth factor 1 (IGF-1), which stimulates cell proliferation and supports the regeneration of skin structures; and transforming growth factor-beta (TGF-β) together with SMAD2, a signaling intermediate that transmits TGF-β signals into the nucleus. The TGF-β/SMAD axis is central to the later phases of wound healing, driving fibroblast activation, collagen deposition, and the orderly remodeling that turns a raw wound into restored, functional tissue. By quantifying all of these transcripts, the team could ask not just whether the wounds healed faster under paraprobiotic treatment, but whether the underlying immunological program had genuinely shifted from a destructive inflammatory state toward a constructive, regenerative one.

The results, as reported in the paper, were striking on both fronts. Paraprobiotic intervention had a major impact on wound healing and on the suppression of bacterial virulence factors—the molecular tools that pathogens use to adhere to tissue, evade immune defenses, and damage host cells. Suppressing virulence rather than bacterial growth represents a fundamentally different therapeutic logic from antibiotics. Instead of imposing a lethal selection pressure that drives resistance, anti-virulence strategies disarm the pathogen, allowing the host’s own defenses to clear the infection. In an era when resistant strains of Pseudomonas aeruginosa and Staphylococcus aureus—two of the most notorious burn wound pathogens, and both listed among the study’s keywords—routinely defeat last-line antibiotics, therapies that reduce the harm bacteria can do, rather than the bacteria themselves, are attracting intense interest.

The gene expression data reinforced the clinical picture. In the paraprobiotic-treated group, the proinflammatory cytokines IL-1, IL-6, and TNF-α were significantly downregulated compared with the control groups, indicating that the treatment had quieted the destructive inflammatory storm in the wound. At the same time, the anti-inflammatory and tissue repair genes—IL-10, IGF-1, SMAD2, and TGF-β—were upregulated, showing that the wound environment had shifted toward the molecular program of active reconstruction. This coordinated pattern matters because healing is not simply the absence of inflammation; it requires a precisely timed transition from the inflammatory phase to the proliferative and remodeling phases. A therapy that simultaneously reduces inflammatory signaling and elevates repair-associated signaling is effectively accelerating that transition, which is consistent with the observed improvement in wound outcomes.

The authors conclude that paraprobiotics possess strong immunomodulatory and regenerative properties that enhance wound repair, making them promising agents for safer and more effective management of infected burn wounds. The framing is important: the value proposition of paraprobiotics is not that they out-kill antibiotics, but that they address the two intertwined problems of infected burns—uncontrolled inflammation and bacterial aggression—with a single intervention that carries a favorable safety profile. Because the therapeutic agent is non-viable, it can be standardized, sterilized, and stored without the cold-chain and contamination concerns that complicate live biotherapeutics. The researchers argue that their results support the development of natural therapeutic approaches designed to maximize patient outcomes in burn care.

As with any early-stage animal study, the usual caveats apply. The experiment involved small groups of mice, and the translation from a murine model to human burn units—a setting where wound depth, patient comorbidities, and polymicrobial infections add layers of complexity—will require substantially more work. The published version is an early-release, peer-reviewed accepted manuscript that remains subject to further editorial edits. Nevertheless, the study adds to a growing body of evidence that the therapeutic potential of probiotic organisms does not end when their viability does. If subsequent studies confirm that inactivated probiotic cells can reliably suppress bacterial virulence and reprogram wound inflammation in humans, paraprobiotics could find a place alongside antibiotics in the treatment of infected burns—offering clinicians a tool that works with the immune system rather than merely against the microbe, at a time when the alternatives are narrowing.

Subject of Research: Paraprobiotic therapy for infected burn wounds in a mouse model

Article Title: Paraprobiotics suppress bacterial virulence and promote anti-inflammatory tissue repair in a murine infected burn wound model

Article References: Salimi, A., Torkamaneh, M., Haghighatshenas, Z., Sakaki, F., Chiani, M., Sohrabi, A., Aghamohammad, S., & Rohani, M. (2026). Paraprobiotics suppress bacterial virulence and promote anti-inflammatory tissue repair in a murine infected burn wound model. Scientific Reports. https://doi.org/10.1038/s41598-026-75233-5

Image Credits: AI Generated

DOI: 10.1038/s41598-026-75233-5

Keywords: paraprobiotics, burn wounds, wound healing, bacterial virulence, inflammatory cytokines, IL-10, TGF-beta, Pseudomonas aeruginosa, Staphylococcus aureus, mouse model, immunomodulation, antibiotic alternatives

Current treatment for the ocular disease relies heavily on corticosteroids, delivered as topical drops, injections into the eye, or oral prednisone. This approach has serious shortcomings. Studies indicate that 30 to 60 percent of patients with HTLV-1-associated uveitis experience recurrent episodes, and long-term steroid exposure can trigger cataracts, glaucoma, macular edema, epiretinal membranes, retinal degeneration, optic nerve atrophy, and bullous keratopathy. Most importantly, corticosteroids suppress inflammation without reducing the number of virus-infected cells or halting disease progression. Newer molecular targeted agents, including the anti-CCR4 antibody mogamulizumab and the immunomodulatory drug lenalidomide, have been explored, but treatment-related inflammation and adverse effects remain significant obstacles. This therapeutic gap motivated a team led by Yaru Zou and Koju Kamoi of Tokyo Medical and Dental University to investigate whether an epigenetic drug already approved for blood cancer could address the root of the ocular inflammation.

The drug in question is valemetostat, marketed as EZHARMIA, a dual inhibitor of the enzymes EZH1 and EZH2 that was approved in 2022 for adult T cell leukemia/lymphoma. Both enzymes are the catalytic components of polycomb repressive complex 2, a molecular machine that silences genes by adding three methyl groups to lysine 27 on histone H3, producing the repressive chromatin mark known as H3K27me3. Previous work had shown that EZH1 and EZH2 are overexpressed, and H3K27me3 deposition increased, in ATL cells and in cells expressing the viral oncoprotein Tax. Dual EZH1/2 inhibitors have also been reported to curb the spontaneous proliferation and exaggerated immune responses of HTLV-1-infected cells in patients with HTLV-1-associated myelopathy. What remained unknown was whether such inhibition could benefit the inflamed eye.

To find out, the researchers built a series of laboratory models centered on ARPE-19 cells, a human retinal pigment epithelial cell line chosen because the retinal pigment epithelium forms the outer blood-retinal barrier and governs retinal immune homeostasis. They exposed these ocular cells to three kinds of T cells: MT-2 cells, which carry transcriptionally active HTLV-1 and express the viral protein Tax; TL-Om1 cells, an ATL-derived line in which the virus is largely silent and Tax is low or absent; and Jurkat cells, which are uninfected and served as controls. In parallel, they treated the T cell lines themselves. Western blotting and quantitative PCR revealed that HTLV-1 infection drove significant upregulation of both EZH1 and EZH2, along with elevated H3K27me3, in infected retinal pigment epithelial cells and in MT-2 cells, with EZH1 protein rising roughly 2.5-fold in infected ocular cells and six-fold in MT-2 cells. This was the first demonstration that HTLV-1 infection induces polycomb-mediated epigenetic changes in retinal cells.

The team then treated the models with valemetostat at 0.01, 0.1, and 1 micromolar for 96 hours, concentrations selected in preliminary experiments because they harmed infected T cells while leaving normal ocular cells, including primary human trabecular meshwork cells, unaffected below 10 micromolar. The results were strikingly dependent on the model. In co-cultures of retinal cells with Tax-positive MT-2 cells, and in retinal cells directly infected with HTLV-1, the drug produced modest but statistically significant reductions in cell viability at the highest dose, accompanied by small increases in late-stage apoptosis. No such effects appeared in co-cultures with TL-Om1 or Jurkat cells. Crucially, the absolute magnitude of apoptosis remained limited, typically only 1 to 3 percent above baseline, indicating that valemetostat is not broadly toxic to retinal cells, an important safety consideration given their role in maintaining vision.

The virological findings were equally nuanced. Valemetostat did not significantly reduce the HTLV-1 proviral load in co-culture systems or in directly infected retinal pigment epithelial cells. However, in MT-2 cells themselves, 1 micromolar valemetostat significantly lowered proviral load and suppressed the messenger RNA levels of both Tax and HBZ, the two hallmark transcripts of the virus. Because MT-2 cells represent the transcriptionally active, highly infectious state of HTLV-1, while TL-Om1 represents latency, the results suggest that the drug’s antiviral effect is gated by the transcriptional status of the infected cell. Within the four-day treatment window, the authors conclude, valemetostat’s benefit to the ocular environment is likely indirect, acting primarily by quieting the most virally active cells rather than by eradicating provirus everywhere.

The most clinically relevant effects emerged in the inflammatory readouts. HTLV-1-infected T cells recovered from the eyes of patients with uveitis are known to secrete copious interleukin-6, interleukin-8, and interleukin-10, all implicated in disease. In the new study, valemetostat produced a dose-dependent increase in the anti-inflammatory cytokine IL-10 in MT-2-containing conditions, significant at 1 micromolar in the co-culture system and across all doses in MT-2 cells. This fits a mechanistic expectation: blocking EZH1/2 removes H3K27me3 marks that repress the IL-10 gene, and prior genetic studies showed that loss of EZH2 directly activates IL-10 transcription in several CD4-positive T cell subsets. Meanwhile, pro-inflammatory signals fell in a context-dependent pattern. IL-12p70 and the chemokine CXCL-10 dropped in co-cultures, IL-6 and IL-8 declined mainly in MT-2 cells, and CCL-2 fell at low doses in the MT-2 co-culture, whereas the chemokine CCL-5 was unchanged in every model.

The drug’s influence on NF-kappaB, the central inflammatory pathway that Tax hijacks to drive both viral replication and cytokine production, was more subdued. Valemetostat modestly reduced NF-kappaB p65 phosphorylation in the MT-2 co-culture at the lowest dose and slightly decreased the nuclear-to-cytoplasmic ratio of p65 in retinal cells stimulated with TNF-alpha, but it did not abolish nuclear translocation. The authors attribute this to the overwhelming strength of Tax-driven NF-kappaB activation, which a 96-hour course of EZH1/2 inhibition may be insufficient to counteract, and to the fact that NF-kappaB and cytokine networks are regulated by many factors beyond polycomb complexes. Immunofluorescence confirmed that valemetostat significantly lowered H3K27me3 in retinal cells exposed to MT-2 cells or directly infected, but not in cells co-cultured with TL-Om1 or Jurkat cells, again underscoring the model dependence of the epigenetic response.

The study also carries a cautionary note about IL-10. Although the cytokine is anti-inflammatory, it can promote the survival of HTLV-1-infected T cells and facilitate immune evasion by impairing dendritic cell antigen presentation and downregulating MHC class I molecules, and patients with aggressive ATL often show abnormally elevated IL-10. The authors therefore suggest that combining EZH1/2 inhibition with IL-10 pathway blockade could prove more effective, noting evidence that IL-10 neutralization sensitizes ATL cells to standard therapies. In the TL-Om1 model of ATL-related ocular infiltration, valemetostat failed to reduce H3K27me3, proviral load, or NF-kappaB activation within the malignant cells, yet it suppressed TL-Om1-induced CXCL10 secretion and induced dose-dependent apoptosis, pointing to a benefit mediated through the inflammatory microenvironment rather than direct tumor killing.

The authors are candid about the limitations. The work relied entirely on in vitro co-cultures and established cell lines, which cannot reproduce the blood-retinal barrier, retinal architecture, or local immune regulation of a living eye, and the intraocular pharmacokinetics of valemetostat after systemic administration remain undefined. Sex as a biological variable could not be assessed because donor-defined primary cells were not used. Even so, the findings establish a proof of concept that an approved epigenetic therapy can counteract HTLV-1-induced chromatin changes in retinal cells, dampen viral transcription in the most active infected cells, and reshape the cytokine milieu that sustains uveitis. Longer treatment studies, in vivo models, and patient-derived systems will be needed to determine whether these modest, context-dependent effects can be translated into a genuine steroid-sparing therapy for one of the most burdensome manifestations of a virus that medicine has long neglected.

Subject of Research: EZH1/2-targeted epigenetic therapy with valemetostat for HTLV-1-associated uveitis

Article Title: Dual impact of EZH1/2-targeted therapy in HTLV-1-associated inflammation: Direct and indirect mechanisms

Article References: Zou, Y., Kamoi, K., Yang, M., Zong, Y., Zhang, J., & Ohno-Matsui, K. (2026). Dual impact of EZH1/2-targeted therapy in HTLV-1-associated inflammation: Direct and indirect mechanisms. iScience, 29(11), Article 117775. https://doi.org/10.1016/j.isci.2026.117775

Image Credits: AI Generated

DOI: 10.1016/j.isci.2026.117775

Keywords: HTLV-1, valemetostat, EZH1, EZH2, H3K27me3, uveitis, epigenetics, PRC2, Tax, IL-10, NF-kappaB, retinal pigment epithelium

The study, led by Deborah Buba of the University of Jos and Ahmadu Bello University in Nigeria, together with colleagues including Peter Mac Asaga of the University Medical Centre Freiburg, compared infections caused by two major African trypanosome species, Trypanosoma congolense and Trypanosoma brucei, in BALB/c mice. These two parasites are responsible for a large share of the animal trypanosomosis burden transmitted by tsetse flies across the continent. T. congolense is notorious among veterinarians for the severe anaemia it produces in cattle, while T. brucei, a close relative of the parasites that cause human sleeping sickness, is known for its ability to invade a wide range of host tissues. Despite their clinical importance, the combined influence of parasite species, inoculation route and host immune response on disease severity had rarely been examined within a single controlled experiment.

The researchers divided the animals into four infected groups of fifteen mice each, with one group receiving T. congolense and another T. brucei by intraperitoneal inoculation, and the remaining two groups receiving the respective parasites intramuscularly. A fifth group of five uninfected mice served as controls. Over the course of the experiment, the team tracked parasitaemia, body weight, rectal temperature and survival, and at defined endpoints they measured packed cell volume, a full panel of haematological indices, serum concentrations of the cytokines interferon-gamma and interleukin-10, and semi-quantitative pathology scores for the liver, spleen and kidney. The design, approved by the Ahmadu Bello University Committee on Animal Use and Care and reported according to the ARRIVE 2.0 guidelines, applied predefined humane endpoints so that no animal was permitted to reach a moribund state.

The survival data were unambiguous. Differences between the groups were highly significant, with a log-rank test yielding a p value below 0.0001. Mice infected intraperitoneally with T. congolense had the shortest median survival of any group, at just nine days. At the other extreme, mice infected intramuscularly with T. brucei survived longest among the infected groups. The two intermediate groups, intramuscular T. congolense and intraperitoneal T. brucei, fell between these poles. What makes this pattern remarkable is what the parasitaemia data did not show: the time until parasites became detectable in the blood and the peak levels they reached were broadly comparable across the infected groups. In other words, the animals that died fastest were not carrying the heaviest parasite burdens, a discordance that strikes at the heart of how virulence is conventionally assessed in laboratory models of trypanosomosis.

Haematological findings reinforced the clinical picture of acute disease. Infected animals developed anaemia, reflected in reduced packed cell volume, along with thrombocytopenia, a depletion of blood platelets. Both changes are hallmarks of African trypanosomosis in livestock and have been linked in previous work to the destruction or removal of red blood cells driven by inflammatory activation of the mononuclear phagocyte system. Earlier studies have implicated interferon-gamma produced by natural killer cells, natural killer T cells and CD8-positive T cells in driving myeloid cell activation and erythrophagocytosis, the engulfment of red blood cells by macrophages, which culminates in the acute anaemia characteristic of these infections. Other mechanisms, including the desialylation of red blood cells by parasite enzymes and cytokine-mediated haemodilution, have been proposed to contribute to the anaemia seen with different trypanosome species.

The cytokine measurements added a layer of nuance. Interferon-gamma, a pro-inflammatory signalling molecule central to the activation of macrophages during protozoal infections, was elevated in all infected animals relative to uninfected controls. However, its concentrations did not distinguish among the four infected groups, meaning this canonical inflammatory signal was similarly engaged regardless of parasite species or inoculation route. Interleukin-10, an anti-inflammatory cytokine that restrains excessive immune activation, told a different story. Its concentrations were higher in mice infected with T. congolense than in those infected with T. brucei, a species-associated pattern that suggests the two parasites elicit qualitatively different immunoregulatory environments within the same inbred host strain.

The histopathological analysis was equally revealing, both for what it showed and for what it did not. Semi-quantitative scoring of the liver, spleen and kidney confirmed that infection inflicted significant damage on all three organs: pathology scores were significantly higher in infected animals than in uninfected controls. Yet when the infected groups were compared with one another, the scores did not differ significantly. The severity of organ-level lesions, like the parasite burden, failed to track with survival. Mice that succumbed rapidly to intraperitoneal T. congolense infection did not carry measurably worse tissue damage than mice that survived longer with T. brucei. This second discordance, between lesion severity and outcome, implies that the functional consequences of infection, rather than the visible structural damage, may be what determines how quickly an animal deteriorates.

Taken together, the results paint a picture in which disease outcome in African trypanosomosis is governed by something more subtle than parasite load or tissue destruction. The authors suggest that species-associated host responses may contribute to disease outcome, although they are careful to note that further mechanistic investigation is required before the causal pathways can be pinned down. One plausible interpretation is that the balance between pro-inflammatory and anti-inflammatory signalling, exemplified here by the species-linked differences in interleukin-10, shapes the physiological toll of infection independently of how many parasites are present or how damaged the organs appear. Excessive or poorly regulated inflammation could accelerate clinical decline even when parasite numbers and histological lesions are comparable, a concept consistent with the broader literature on immunopathology in trypanosome infections.

The findings also carry practical implications for experimental design in trypanosomosis research. Laboratory models of animal African trypanosomosis have long been criticised for their reliance on syringe-passaged parasites and laboratory rodents, which can diverge from the natural tsetse-transmitted infections seen in clinically relevant livestock hosts. The demonstration that inoculation route measurably alters survival, with intramuscular delivery of T. brucei producing the most prolonged course, echoes earlier work showing that route of inoculation influences the virulence of both T. congolense and T. brucei brucei in mice. Researchers selecting a challenge model should therefore be aware that the route of infection is not a neutral variable but an active determinant of disease tempo, one that could confound comparisons between studies or mask genuine differences in parasite virulence or drug efficacy.

For the veterinary and medical communities, the study underscores a message that has been building across the trypanosomosis literature: virulence is a property of the interaction between parasite and host, not of the parasite alone. Recent work has revealed that African trypanosomes occupy unexpected tissue niches, including the skin and adipose tissue, where they may persist and adapt in ways that influence transmission and disease. The new data add a controlled, quantitative demonstration that two closely related parasite species, delivered at comparable infectious doses into the same host strain, can produce the same parasite burden and the same organ pathology while killing at different speeds and provoking different cytokine profiles. Untangling the mechanisms behind these discordances, particularly the role of interleukin-10 and other immunoregulatory pathways, may ultimately inform approaches that target the damaging host response as well as the parasite itself, an increasingly recognised strategy for diseases in which immunopathology drives the clinical picture.

Subject of Research: Comparative pathogenicity and multi-organ histopathology of Trypanosoma congolense and Trypanosoma brucei infection in mice

Article Title: Comparative Pathogenicity and Semi-quantitative Multi-organ Histopathology of Trypanosoma congolense and Trypanosoma brucei Infection in Mice

Article References: Buba, D., Adamu, S., Mohammed, B., Jatau, I. D., & Asaga, P. M. (2026). Comparative Pathogenicity and Semi-quantitative Multi-organ Histopathology of Trypanosoma congolense and Trypanosoma brucei Infection in Mice. Acta Parasitologica, 71(5), Article 232. https://doi.org/10.1007/s11686-026-01417-8

Image Credits: AI Generated

DOI: 10.1007/s11686-026-01417-8

Keywords: Trypanosoma congolense, Trypanosoma brucei, animal African trypanosomosis, pathogenicity, inoculation route, anaemia, histopathology, cytokines, IFN-gamma, IL-10, murine model, parasitaemia

Extracellular vesicles, or EVs, are small lipid-enclosed particles released by virtually every cell type in the body, including tumor cells. For decades they were dismissed as cellular debris, but they are now recognized as a fundamental communication system: EVs ferry proteins, lipids and nucleic acids between cells, influencing processes such as immune regulation, angiogenesis and metastatic preparation. Because the molecular cargo of an EV reflects the cell that released it, tumor-derived vesicles are increasingly viewed as a liquid biopsy window into the biology of a cancer without the need for invasive tissue sampling. Cytokines, the small proteins that immune and stromal cells use to signal to one another, are known to shape tumor development and progression, and the question driving this study was whether cytokines bound to or packaged within EVs form a measurable and clinically informative signature in the bloodstream.

To answer it, the researchers isolated EVs from plasma using ultracentrifugation, a technique that spins samples at extremely high speeds to pellet vesicles out of solution. They applied a rigorous characterization pipeline to confirm that the particles they recovered were genuine EVs: transmission electron microscopy provided direct visualization of vesicle morphology, nanoparticle tracking analysis quantified particle size and concentration, flow cytometry probed surface markers, and western blotting verified the presence of canonical EV-associated proteins. The same isolation approach was applied to breast cell lines grown in the laboratory, giving the team a controlled comparison against vesicles produced by healthy breast tissue cells.

The clinical core of the study involved 46 patients with ER+ breast cancer enrolled in the Neoletexe trial, alongside 13 healthy individuals as controls. EV-associated cytokines were profiled using a Luminex multiplex assay, a bead-based platform capable of measuring dozens of proteins simultaneously from a small sample volume. Crucially, the researchers sampled patients at three timepoints: before treatment began (T0), and at two points during neoadjuvant endocrine therapy (T1 and T2). This longitudinal design meant that each patient could serve partly as her own control, revealing how the vesicle-bound cytokine landscape shifted as aromatase inhibitors stripped estrogen from the equation and the tumor responded, or failed to respond, to the hormonal blockade.

The headline finding was that three EV-associated cytokines were significantly elevated in ER+ breast cancer patients compared with healthy individuals: interleukin 10 (IL-10), interleukin 12 (IL-12) and interferon gamma inducible protein 10, better known as IP-10 or CXCL10. Each of these molecules carries immunological weight. IL-10 is generally an anti-inflammatory cytokine that can dampen immune attacks on tumors, IL-12 is a potent activator of T cells and natural killer cells, and IP-10 is a chemokine recruited into action by interferon gamma that guides immune cells to sites of inflammation and, in many cancers, is intertwined with the tumor microenvironment’s immune landscape. Their enrichment on circulating vesicles in patients suggests that EV-associated cytokines capture disease-relevant immune signaling that differs measurably from the healthy state.

The IP-10 result gained independent support from tumor tissue analysis. Using gene expression data, the team found that CXCL10, the gene encoding IP-10, was overexpressed in breast cancer tissue relative to both normal and benign breast tissue, a pattern corroborated through the GEPIA analysis platform drawing on The Cancer Genome Atlas. This convergence between the vesicle protein measurements in blood and the transcriptional activity inside tumors strengthens the argument that EV-associated IP-10 genuinely reflects processes occurring at the disease site rather than incidental background variation. It is exactly this kind of cross-validation that candidate biomarkers need before they can move from exploratory science toward clinical utility.

Perhaps the most technically interesting result concerned how the vesicle-bound cytokines behaved once endocrine therapy started. Levels of EV-associated IL-10 and IL-12 decreased significantly during NET, indicating that the treatment does not merely shrink or slow the tumor but measurably reshapes the immune signaling carried by circulating vesicles. Notably, the treatment-associated changes were more pronounced in the EV-associated cytokines than in the corresponding free-circulating cytokines measured in the same plasma samples, and more pronounced than changes in cytokine gene expression measured in tumor tissue from a subset of the same patients. This suggests that vesicle-packaged cytokines act as a kind of amplifier or concentrator of systemic immune signals, potentially offering greater analytical sensitivity than conventional plasma cytokine assays, which have long been hampered by low concentrations, short half-lives and interference from non-specific binding.

The study was not without its sobering results. When the researchers asked whether any of the measured cytokines predicted treatment response, as assessed by the change in Ki-67, the standard proliferation marker used to gauge how actively tumor cells are dividing under therapy, only eotaxin, a chemokine best known for recruiting eosinophils, showed a significant association. None of the three disease-elevated cytokines tracked treatment response in this way. This dissociation between disease detection and response prediction is an important nuance: a marker can be excellent at distinguishing patients from healthy individuals yet still fail to forecast how an individual tumor will behave under therapy. The authors are careful to frame their findings as evidence that EV-associated cytokines reflect disease- and treatment-related changes, while emphasizing that further studies are required to determine their potential clinical relevance as biomarkers.

Methodologically, the study demonstrates the value of triangulating across molecular compartments. By measuring the same cytokines in three formats, vesicle-bound in plasma, free-circulating in plasma, and as gene expression in tumor tissue, the researchers could show that the vesicle fraction carries complementary rather than redundant information. This matters because the field of liquid biopsy has often been dominated by circulating tumor DNA and extracellular RNA, while the protein cargo of EVs, and cytokines in particular, has remained comparatively underexplored. The finding that EV-associated signals respond more dynamically to endocrine therapy than either free cytokines or tumor transcript levels hints that vesicles may stabilize and enrich labile signaling proteins, protecting them from degradation and protease activity in the bloodstream.

The broader implications reach into how ER-positive breast cancer is monitored. Neoadjuvant endocrine therapy is typically given for months before surgery, and clinicians currently rely on imaging and serial biopsies to judge whether the regimen is working. A blood test that captures treatment-induced shifts in tumor-associated immune signaling could, if validated, allow earlier and less invasive assessment. The Norwegian team’s work, funded in part by Akershus University Hospital and the Norwegian Breast Cancer Research Network and conducted under ethical approval from the Regional Ethics Committee of Southeast Norway, provides a carefully characterized early step in that direction. With 46 patients and 13 controls, the cohort is modest, and ultracentrifugation-based EV isolation, while thorough, is labor-intensive and not yet standardized across laboratories. Larger, multi-center studies with standardized vesicle isolation and longitudinal follow-up will be needed to establish whether IL-10, IL-12 and IP-10 on circulating vesicles can graduate from candidate markers to clinically actionable tools. For now, the study adds a compelling piece to the growing evidence that the smallest messengers in our blood may carry some of the biggest clues about cancer.

Subject of Research: Extracellular vesicle-associated cytokines as circulating biomarkers in ER-positive breast cancer and neoadjuvant endocrine therapy

Article Title: Analysis of circulatory extracellular vesicle–associated cytokines as candidate disease-associated markers in ER-positive breast cancer

Article References: Huynh, H. M., Nawaz, M. S., Jabeen, S., Bjørnetrø, T., Geisler, J., Kristensen, V., & Tahiri, A. (2026). Analysis of circulatory extracellular vesicle–associated cytokines as candidate disease-associated markers in ER-positive breast cancer. BMC Cancer. https://doi.org/10.1186/s12885-026-17052-5

Image Credits: AI Generated

DOI: 10.1186/s12885-026-17052-5

Keywords: extracellular vesicles, cytokines, ER-positive breast cancer, liquid biopsy, biomarkers, neoadjuvant endocrine therapy, IL-10, IL-12, IP-10, CXCL10, aromatase inhibitors, Neoletexe trial