Researchers first integrated 4,646 predicted quercetin targets with 1,602 ICH-associated genes, identifying 657 shared genes that mapped to 642 mouse orthologs. They combined these targets with exploratory differential-expression results from one mouse brain transcriptomic dataset and an endoplasmic-reticulum-stress-related reference set, producing 29 candidate genes. Functional enrichment implicated TNF and IL-17 signaling, leukocyte migration, stress responses and extracellular matrix processes.

A protein-protein interaction analysis ranked the 29 candidates using five centrality methods. Seven genes appeared in all five top-10 lists and were designated consensus hubs: Il1b, Mmp9, Timp1, Myc, Fos, Hmox1 and Socs3. In the discovery dataset, five hubs had higher expression after ICH than in controls and each had an area under the ROC curve greater than 0.9. In an independent dataset, six hubs were differentially expressed and also had AUC values above 0.9, although these exploratory analyses involved only five ICH and five control samples per dataset.

Molecular docking produced putative binding poses between quercetin and all seven hub proteins. The strongest predicted binding scores were reported for Fos, Hmox1, Il1b, Mmp9 and Timp1, while Socs3 and Myc had moderate predicted affinity. These computational estimates were interpreted as hypothesis-generating and do not demonstrate direct biochemical binding or target engagement.

For experimental validation, researchers used male C57BL/6 mice aged 6 to 8 weeks. ICH was induced by injecting collagenase into the striatum, with sham-operated animals receiving saline. Groups of six mice received intraperitoneal quercetin at 25, 50 or 100 mg/kg per administration, twice at 0.5 and 12 hours after hemorrhage, for total 24-hour administered doses of 50, 100 and 200 mg/kg. A separate group received dexamethasone at 2 mg/kg per administration on the same schedule as an anti-inflammatory comparator. The quercetin and dexamethasone regimens were described as literature-informed exploratory designs rather than direct replications.

At 24 hours, brain water content was significantly higher after ICH than in sham-operated mice. Quercetin at 100 mg/kg per administration reduced brain water content compared with untreated ICH, as did dexamethasone; the difference between those two groups was not significant. In perihematomal tissue, quercetin at 50 and 100 mg/kg reduced Il1b expression, while all three doses reduced Mmp9 and Fos expression. Timp1 expression increased after all three doses. Hmox1 increased selectively at the high dose, and Socs3 rose dose-dependently, while Myc was not significantly altered by treatment.

Serum measurements in mice showed increases in IL-1β, IL-6, TNF-α and MMP-9 after ICH. The 25 mg/kg quercetin dose did not significantly reduce any of these markers relative to untreated ICH. At 50 mg/kg, quercetin reduced all four markers, while at 100 mg/kg it produced reductions in all four that were not significantly different from sham levels. Dexamethasone showed a similar pattern, but the study did not establish equivalence between the treatments.

To assess disease relevance in humans, investigators analyzed paired perihematomal and remote non-hemorrhagic brain tissues from six ICH patients undergoing clinically indicated hematoma evacuation. Perihematomal tissue had higher IL1B, MMP9, TIMP1 and HMOX1 messenger RNA than matched remote tissue. Western blotting confirmed higher IL-1β, MMP-9 and TIMP1 proteins, and immunohistochemistry showed greater MMP-9 immunoreactivity and a larger MMP-9-positive area in perihematomal samples. These observations support the relevance of selected targets to human ICH pathology, but the patients did not receive quercetin, so the tissue data do not demonstrate quercetin-specific efficacy or target engagement.

Serum was also collected within 24 hours of symptom onset from six ICH patients and six age- and sex-approximated healthy controls. IL-1β, IL-6, IL-10, IL-17A and TNF-α concentrations were higher in patients. The human cohort was small and observational, while the mouse experiments were limited to males, one collagenase model, small groups of six and a single 24-hour endpoint. Hematoma or lesion volume, neurological and behavioral outcomes, histopathology, blood-brain barrier integrity and cell-specific mechanisms were not assessed. The results therefore support an acute experimental association between quercetin and lower inflammatory, matrix-remodeling and edema-related markers, not clinical benefit in people with ICH.

Subject of Research: Preclinical assessment of quercetin in experimental intracerebral hemorrhage

Article Title: Quercetin attenuates acute inflammation and extracellular matrix remodeling after intracerebral hemorrhage: transcriptomics-informed network pharmacology and experimental validation

Article References: Shu, J., Feng, K., Pan, A., Li, G., Liu, K., & Feng, L. (2026). Quercetin attenuates acute inflammation and extracellular matrix remodeling after intracerebral hemorrhage: transcriptomics-informed network pharmacology and experimental validation. Frontiers in Pharmacology, 17, Article 1930434. https://doi.org/10.3389/fphar.2026.1930434

Image Credits: AI Generated

DOI: 10.3389/fphar.2026.1930434

Keywords: intracerebral hemorrhage, quercetin, neuroinflammation, extracellular matrix, network pharmacology, mouse model, MMP-9, IL-1β, human brain tissue, transcriptomics, attenuates, acute

The work focused on chimeric RNAs, or chRNAs, formed when sequences from separate genomic loci are combined within one transcript. Researchers had previously linked some chimeric transcripts to cancer-associated chromosomal rearrangements, but earlier work had also shown that RNA-level trans-splicing can generate chRNAs and functional fusion proteins without corresponding changes in genomic structure. Isolated examples had been reported in normal contexts, including JAZF1-JJAZ1 in endometrial fibroblasts and PAX3-FOXO1 during muscle differentiation. The new study, described in a research highlight published in Cell Research, asks whether additional trans-spliced RNAs occur widely in mammalian tissues and whether they can make functional proteins in normal immune cells.

To map chRNAs in mouse macrophages, the researchers combined long-read Oxford Nanopore direct RNA sequencing with short-read sequencing, computational analysis, PCR and Sanger sequencing. They also used NanoString junction-specific profiling, an orthogonal hybridization-based method for testing predefined RNA junctions. More than 30,000 candidate chimeric RNAs were detected. Many joined genes on different chromosomes or separated by large genomic distances, and numerous transcripts changed after inflammatory stimulation. That regulation argues that chRNA formation is not merely random noise generated during transcription. Instead, the joining of RNA sequences appears to respond to the physiological state of the cell, although the researchers did not directly test the function of every candidate transcript.

Validating such molecules presents a central technical problem. Short-read sequencing usually involves reverse transcription, and template switching during reverse transcription or library preparation can create artificial sequence junctions that resemble genuine RNA fusions. Direct RNA sequencing avoids that particular source of error, while the independent NanoString assay and PCR-based tests provide additional ways to confirm selected junctions. Agreement among these methods strengthened the case that the identified chRNAs are endogenous. The technologies did not recover identical transcript sets, however. Abundance, isoform structure, sequencing chemistry and assay sensitivity can all affect which low-level chRNAs are detected, leaving standardized validation criteria as an important requirement for future studies.

The analysis also connected chRNA production with the three-dimensional organization of the genome. Inflammatory stimulation increased contacts between several parental genomic loci involved in forming chRNAs. Depleting CTCF, a protein that helps organize chromatin loops, reduced those contacts and decreased chRNA production without substantially altering expression of the parent genes. This supports a model in which the physical arrangement of chromosomes helps determine which independently transcribed RNAs can be connected. Proximity alone is unlikely to be sufficient, though. The study did not resolve how two transcripts are selected, aligned and joined, or which splice-site features, RNA-binding proteins, transcriptional timing or regulatory sequences guide the process. Genomic architecture may therefore facilitate RNA-level gene joining without being its sole determinant.

The strongest functional evidence came from the Gsdmd-Tmem106a chimera. Its RNA joined exons 1–2 of Gsdmd with exons 6–9 of Tmem106a without an accompanying chromosomal rearrangement. Translation produced an unannotated GSDMD-TMEM106A fusion protein containing the membrane-associated N-terminal region of GSDMD and a shifted C-terminal region derived from TMEM106A. GSDMD normally acts as an executor of pyroptosis: inflammatory caspase-mediated cleavage releases its N-terminal domain, which oligomerizes in membranes to form pores. Those pores promote membrane permeabilization and IL-1β release. The fusion protein localized to the plasma membrane and associated with activated GSDMD-NT domains, adding a regulatory layer to an established inflammatory pathway.

Experiments showed that the effect was not simply a consequence of making more GSDMD. The chimeric RNA was expressed at less than 10% of the level of parental Gsdmd. Adding an amount of GSDMD-TMEM106A-encoding messenger RNA equal to that lower level nearly doubled IL-1β release when supplied alongside GSDMD-encoding messenger RNA, whereas a comparable increase in GSDMD had little effect. Removing the TMEM106A-derived C-terminal segment abolished the enhancement. These results indicate that the fusion protein performs a specific function rather than acting merely as an additional source of GSDMD. The work also provides a concrete example of why conventional expression measurements alone can miss biologically important activity: a relatively scarce transcript can encode a protein with a large effect on cellular behavior.

Complementary mouse genetic models established relevance during infection and systemic inflammation. A GSDMD-TMEM106A-MYC knock-in allowed the fusion protein to be detected directly, while a Gsdmd-Tmem106aStop model selectively prevented translation of the fusion while preserving both parental genes. Eliminating GSDMD-TMEM106A increased bacterial burden after infection with Salmonella Typhimurium but protected mice from lethal endotoxemia. Increasing fusion activity produced the opposite pattern, improving bacterial clearance while worsening inflammatory pathology. The chimera therefore appears to help tune a trade-off: preserving an effective response against intracellular bacteria can also intensify inflammatory injury. The experiments were performed in mice, so they do not establish that the same quantitative balance operates in people.

The findings may not transfer directly from mice to humans. The researchers identified more than 900 chRNAs in human monocyte-derived macrophages and detected chRNAs involving the same parent genes in both mouse and human cells, but they did not detect GSDMD-TMEM106A itself in the human macrophages examined. Conservation of the genes from which a chimera is assembled therefore does not guarantee conservation of the assembled RNA. Species differences in exon structure, splice-site compatibility, regulatory sequences, RNA-binding factors and genome organization could all affect whether a particular chRNA is generated. More broadly, the study suggests that cellular responses may depend not only on how strongly individual genes are expressed, but also on which transcripts become connected, when they are translated and whether the resulting proteins are functional.

That implication reaches beyond immune biology. Stimulus-responsive chRNAs could contribute to regulatory networks in development, nervous-system function, tissue repair, aging and disease, but the present study does not demonstrate such roles. Its strongest conclusion is that mammalian immune cells contain a large, regulated landscape of chimeric RNAs and that at least one member can encode a functional fusion protein in vivo. By linking chromatin contacts and CTCF-dependent genome organization to RNA joining, and then to the control of pyroptosis, the work reframes the transcriptome as more than a collection of transcripts encoded one gene at a time. It also exposes a deeper question for future research: how far the three-dimensional organization of the genome determines which genes become functionally connected at the RNA level, and how often that connection creates a protein with a biological role that would be missed by measuring parent-gene expression alone.

Subject of Research: Inflammation-induced chimeric RNAs in mammalian immune cells and fusion-protein control of pyroptosis

Article Title: Functional chimeric RNAs expand the mammalian proteome

Article References: Xie, Z., & Li, H. (2026). Functional chimeric RNAs expand the mammalian proteome. Cell Research. https://doi.org/10.1038/s41422-026-01309-6

Image Credits: AI Generated

DOI: 10.1038/s41422-026-01309-6

Keywords: chimeric RNA, pyroptosis, inflammation, immune cells, fusion proteins, CTCF, genome organization, macrophages, IL-1β, RNA sequencing, Functional, chimeric

Researchers treated SK-Hep1 cells with TGF-β1, IL-1β or the two agents together. Western blotting and immunofluorescence were used to assess mesenchymal marker expression, while wound-healing and Matrigel transwell invasion assays evaluated migration and invasion. The selective p38 inhibitor SB202190 was then used to examine whether the observed cellular responses depended on p38 signaling. These methods confined the investigation to cultured cells and did not involve animals, patients or clinical outcomes.

According to the abstract, TGF-β1 induced fibronectin and N-cadherin expression and increased the cells’ migratory and invasive capacities. Adding IL-1β further enhanced those responses. At the signaling level, IL-1β markedly increased p38 MAPK phosphorylation and strengthened TGF-β1-mediated SMAD2/3 phosphorylation and nuclear trans-localization. SB202190 decreased fibronectin and N-cadherin expression and reduced migration and invasion, supporting a functional contribution from p38 MAPK to the measured phenotype.

The study therefore supports the conclusion that IL-1β can potentiate selected TGF-β1-induced responses in SK-Hep1 cells through a p38 MAPK pathway linked to TGF-β/SMAD signaling. However, the evidence presented here comes from a single cell line and its reported in vitro assays. The summary does not establish whether the same mechanism operates in primary tumor tissue, other hepatocellular carcinoma models, immune cells or patients, and it provides no evidence that p38 inhibition or anti-inflammatory treatment improves clinical outcomes. The authors’ proposal for further investigation of anti-inflammatory strategies should consequently be understood as a research direction rather than a demonstrated therapeutic approach.

Subject of Research: In vitro analysis of IL-1β modulation of TGF-β1-driven mesenchymal phenotypes and migration in SK-Hep1 cells

Article Title: Interleukin-1β potentiates transforming growth factor-β-induced fibronectin expression, migration, and invasiveness of mesenchymal-like SK-Hep1 cells via p38 mitogen-activated protein kinase–SMAD2/3 crosstalk

Article References: Fatima, S., Regmi, B., Hwang, S., Kim, M. Y., Baik, S. K., Jung, P. Y., & Eom, Y. W. (2026). Interleukin-1β potentiates transforming growth factor-β-induced fibronectin expression, migration, and invasiveness of mesenchymal-like SK-Hep1 cells via p38 mitogen-activated protein kinase–SMAD2/3 crosstalk. Molecular Biology Reports, 53(1), Article 1580. https://doi.org/10.1007/s11033-026-12763-1

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12763-1

Keywords: IL-1β, TGF-β1, SK-Hep1 cells, hepatocellular carcinoma, p38 MAPK, SMAD2/3, fibronectin, N-cadherin, cell migration, cell invasion, mesenchymal phenotype, Interleukin-1

The investigation began with a large-scale mapping exercise. The researchers combined single-cell proteomics data acquired through mass cytometry, a technique known as CyTOF that measures dozens of proteins on individual cells, with public transcriptomic datasets from the Gene Expression Omnibus and The Cancer Genome Atlas. This integrative analysis revealed that CD7 is not confined to a single obscure leukemia subtype. Instead, it appears across most AML subgroups, albeit at strikingly heterogeneous levels, and is consistently enriched on early-stage myeloid cells. That pattern is significant because immature cells are thought to harbor much of leukemia’s regenerative capacity, suggesting that CD7 expression marks a population with stem-like behavior and clinical menace.

To move beyond correlation, the team built cell lines with distinct CD7 expression levels and performed functional perturbation experiments, using short hairpin RNA to silence the protein where it was abundant and to introduce it where it was absent. The results were unambiguous. CD7 promoted leukemic cell fitness on several fronts simultaneously: it accelerated proliferation, pushed cells through the cell cycle more efficiently, and suppressed differentiation, the process by which immature blood cells would normally mature and lose their malignant potential. In other words, CD7 helps leukemia cells stay young, divide quickly, and refuse to grow up, a combination that oncologists recognize as a recipe for aggressive disease.

The most consequential finding, however, concerned chemotherapy. When CD7-expressing cells were exposed to cytarabine, a nucleoside analog that terminates DNA synthesis, and daunorubicin, an anthracycline that damages DNA and poisons topoisomerase II, they survived at doses that killed their CD7-negative counterparts. This resistance was not a side effect of faster growth or slower drug uptake alone. Instead, the researchers traced it to a signaling cascade centered on nuclear factor kappa B, the transcription factor better known as NF-κB, which sits at the crossroads of inflammation, immunity, and cell survival.

Using western blotting and immunofluorescence, the team showed that CD7-positive AML cells displayed enhanced activation of the NF-κB pathway, visible as the characteristic nuclear translocation of NF-κB subunits and the degradation of its inhibitor, IκBα. Once active, NF-κB reprogrammed gene expression in two directions that both favor drug survival. First, it drove transcriptional upregulation of P-glycoprotein 1, the famous multidrug efflux pump that expels chemotherapeutic agents from the cell before they can inflict lethal damage. Second, it sustained the expression of XIAP, the X-linked inhibitor of apoptosis protein, which blocks the caspase enzymes that execute programmed cell death. Together, these two arms of the NF-κB program allow CD7-positive leukemia cells to pump out the poison and refuse to die.

RNA sequencing reinforced the mechanistic picture. Gene set enrichment analysis and pathway mapping showed that the transcriptional landscape of CD7-positive cells was dominated by NF-κB target genes and inflammatory signaling modules, consistent with the protein-level observations. The study also considered other drug transport machinery, including the nucleoside transporter hENT1 and the efflux protein MRP4, which are relevant to cytarabine handling, but the dominant, CD7-dependent axis ran through P-glycoprotein 1 and XIAP under NF-κB control. This level of mechanistic detail matters because it converts CD7 from a statistical risk factor into a defined, targetable circuit.

Perhaps the most biologically intriguing part of the story involves the tumor microenvironment. The bone marrow of an AML patient is an inflammatory place, bathed in cytokines released by both malignant and stromal cells. The researchers found that inflammatory cytokines, specifically interleukin-1 beta and tumor necrosis factor alpha, selectively amplified NF-κB activation in a CD7-dependent manner. In cells lacking CD7, the same cytokines produced a far weaker response. This suggests that CD7 acts as an antenna that lets leukemia cells exploit the cytokine-rich soil of the marrow, converting the body’s own inflammatory signals into a survival program that includes drug efflux and apoptosis evasion. Chemotherapy itself can worsen this environment, raising the possibility of a vicious cycle in which treatment-induced inflammation further hardens the remaining leukemia cells against the next round of drugs.

The clinical implications are immediate and concrete. CD7 is already a familiar target in hematology because of its prominence on T-cell acute lymphoblastic leukemia, and CD7-directed immunotherapies, including antibody-drug conjugates and CAR-T cell constructs, are in active clinical development for T-cell malignancies. The new findings provide a mechanistic rationale for extending that arsenal to CD7-positive AML, particularly in patients whose disease has proven refractory to standard induction chemotherapy. Beyond direct targeting, the study highlights the downstream nodes as vulnerabilities in their own right: inhibitors of NF-κB signaling, P-glycoprotein function, or XIAP activity could, in principle, resensitize CD7-positive blasts to cytarabine and daunorubicin, restoring the effectiveness of drugs that have anchored AML therapy for half a century.

There are, of course, caveats that temper the excitement. NF-κB is a double-edged sword in human physiology, essential for immune defense, and systemic blockade carries well-known risks, so any therapeutic strategy will need to navigate toxicity carefully. The study relied partly on cell line models, and although the authors anchored their analysis in patient-derived single-cell data and samples collected with written informed consent under ethics approval from the Institute of Hematology and Blood Diseases Hospital, prospective validation in patient cohorts will be essential before CD7 becomes a routine stratification biomarker. Heterogeneous expression across subgroups also means that any CD7-directed approach will need companion diagnostics to identify the patients most likely to benefit.

Even with those qualifications, the study represents a satisfying resolution to a long-standing puzzle. A marker that clinicians have measured and worried about for years now has a coherent biological job description: it keeps leukemic cells immature and proliferative, arms them with drug pumps and anti-death machinery through NF-κB, and tunes them to the inflammatory chorus of the bone marrow. The work was supported by China’s National Key Research and Development Program and the National Natural Science Foundation of China, and it exemplifies how single-cell technology combined with classical molecular biology can turn a correlation into a mechanism. For patients with CD7-positive AML, a group that has long carried a worse prognosis, the message is one of cautious optimism: the enemy’s armor has been mapped, and each plate of that armor is now a potential point of attack.

Subject of Research: Mechanism by which CD7 promotes chemoresistance in acute myeloid leukemia through cytokine-dependent NF-κB signaling

Article Title: CD7 drives chemoresistance in acute myeloid leukemia via cytokine-dependent NF-κB signaling

Article References: Ren, C.-S., Shao, N., Yuan, Y., Cheng, T., Yi, H., Xu, H., Li, S.-M., Wang, D.-B., & Zhang, X.-E. (2026). CD7 drives chemoresistance in acute myeloid leukemia via cytokine-dependent NF-κB signaling. Journal of Experimental & Clinical Cancer Research. https://doi.org/10.1186/s13046-026-03835-y

Image Credits: AI Generated

DOI: 10.1186/s13046-026-03835-y

Keywords: acute myeloid leukemia, CD7, chemoresistance, NF-κB, cytarabine, daunorubicin, P-glycoprotein 1, XIAP, IL-1β, TNF-α, drug efflux, single-cell proteomics

The research team, led by Meng Xie and corresponding author Li Zhao, enrolled 219 children who presented with febrile seizures between January 2023 and December 2024. Of these, 118 had simple febrile seizures and 101 had complex febrile seizures. The investigators drew blood within thirty minutes of admission and measured serum concentrations of the pro-inflammatory cytokines interleukin-1 beta and interleukin-6, along with 25-hydroxyvitamin D, the standard circulating measure of vitamin D status. Additional inflammatory biomarkers were assayed as candidate predictors. The design was retrospective and single-center, meaning the children were identified from existing clinical records rather than followed prospectively, and all measurements came from a single hospital laboratory, an important caveat when generalizing the findings to other settings with different assay platforms and patient populations.

The biological rationale for choosing these three markers is grounded in what is known about the neuroimmunology of febrile seizures. Interleukin-1 beta is a central mediator of fever and neuronal excitability; it promotes the release of prostaglandin E2 in the hypothalamus and can enhance glutamatergic signaling in the hippocampus, lowering the seizure threshold during fever. Interleukin-6, by contrast, has a more complicated dual role, participating in both pro- and anti-inflammatory signaling in the central nervous system. Vitamin D adds a third dimension, because the active hormonal form of the vitamin regulates immune responses and has documented anticonvulsant and neuroprotective properties, while deficiency states have been repeatedly linked to increased seizure susceptibility in pediatric populations. The study’s central question was whether the combined pattern of these three circulating factors could discriminate between the two seizure types better than any single marker or clinical impression alone.

Using multivariable logistic regression, the researchers identified all three markers as independent predictors of complex febrile seizures, each with a distinct directional signature. Higher interleukin-1 beta levels were associated with increased odds of a complex seizure, with an adjusted odds ratio of 1.085 per unit increase, a 95 percent confidence interval of 1.042 to 1.130, and a p value below 0.001. Interleukin-6 and 25-hydroxyvitamin D moved in the opposite direction: both were independently associated with lower odds of complex febrile seizures, with adjusted odds ratios of 0.919 and 0.889 respectively, and both confidence intervals excluding the null value. The inverse association for interleukin-6 is intriguing and may reflect its immunoregulatory, anti-inflammatory arm becoming dominant in children whose febrile response is more contained, though the authors present the association as predictive rather than mechanistic.

From these regression coefficients the team constructed a nomogram, a graphical scoring instrument that converts a patient’s individual biomarker values into points, sums them, and translates the total into an estimated probability of complex febrile seizure. Nomograms have long been popular in oncology risk prediction and are increasingly applied to pediatric diagnostics because they compress a multivariable model into a single bedside-usable chart that requires no calculator or software. In this case, a physician measuring interleukin-1 beta, interleukin-6, and 25-hydroxyvitamin D on admission could read off a percentage that quantifies how likely the seizure is to be complex, supplementing the clinical history rather than replacing it.

The model’s performance statistics were strong for a three-variable biomarker panel. The area under the receiver operating characteristic curve, a standard measure of discrimination that expresses the probability that a randomly chosen complex case is ranked above a randomly chosen simple case, reached 0.860 with a 95 percent confidence interval of 0.813 to 0.907. This combined score significantly outperformed each individual biomarker on its own, with all pairwise comparisons reaching statistical significance. At the optimal cutoff of 61.3 percent predicted probability, the model achieved a sensitivity of 84.2 percent, correctly identifying most complex seizures, and a specificity of 77.1 percent, correctly clearing most simple ones. In practical terms, roughly five out of six complex febrile seizures would be flagged by the tool, while about three of four simple seizures would be correctly classified as low risk.

Discrimination alone is not sufficient for a clinical prediction tool, and the authors addressed this with two additional analyses. Calibration, the agreement between predicted probabilities and observed outcomes, was assessed with the Hosmer-Lemeshow test, which yielded a chi-square statistic of 13.848 with eight degrees of freedom and a p value of 0.086, indicating no statistically significant miscalibration. Decision curve analysis, a method that quantifies the net clinical benefit of acting on a model’s predictions across a range of decision thresholds, confirmed a positive net benefit across clinically relevant probabilities. To guard against overfitting in a modest sample, the team employed 1000 bootstrap resampling iterations for internal validation, a standard technique that simulates repeated sampling from the same population to estimate how the model would perform on new patients from the same source.

One of the more clinically important findings concerns age. Febrile seizure guidelines and prognosis differ meaningfully between younger and older children, and any risk tool that behaves inconsistently across age strata would be difficult to deploy. The researchers therefore performed subgroup analyses dividing the cohort into children aged three years or younger and children older than three, and supplemented this with continuous interaction testing for effect modification. The model’s discrimination was nearly identical across the two strata, with AUCs of 0.860 and 0.865 respectively, and all interaction p values exceeded 0.05, indicating that the biomarker relationships did not differ significantly by age. The authors also report that performance remained consistent across subtypes of complex febrile seizures, strengthening the case for the tool’s general applicability within the studied population.

The implications, if the findings are replicated, could be substantial for emergency pediatric care. A rapid, objective classification at the front door could guide decisions about lumbar puncture, neuroimaging, admission versus discharge, duration of observation, and the intensity of parental counseling, potentially reducing both unnecessary interventions for low-risk children and premature discharge of high-risk ones. The authors are careful to frame the nomogram as an adjunctive risk-stratification instrument, and they note a practical constraint: its use depends on the availability of rapid multiplex cytokine testing, which is not yet routine in many emergency departments. The retrospective, single-center design, the modest sample of 219 children, and the need for external validation in independent cohorts with different ethnic, geographic, and laboratory contexts all temper enthusiasm appropriately. Still, the study adds to a growing literature suggesting that the immune fingerprint of a febrile illness, read through a handful of serum markers, carries information that clinical history alone cannot provide.

The work also highlights a broader shift in pediatric neurology toward quantitative, biomarker-informed risk stratification. Where previous generations of clinicians relied on seizure semiology recalled under stress, the combination of interleukin-1 beta, interleukin-6, and vitamin D offers a measurable, reproducible snapshot of the host response at the moment of presentation. The research was funded by the Scientific Research Fund of the Hebei Health Commission, received ethical approval from Shijiazhuang People’s Hospital, and was published open access, making the full model details available to other research groups seeking to validate or refine the approach. Whether this particular three-marker panel becomes standard practice will depend on prospective multicenter trials, but the study demonstrates that a simple, transparent statistical tool built from routine blood tests can meaningfully sharpen one of the most common and consequential diagnostic judgments in pediatric emergency medicine.

Subject of Research: A biomarker-based nomogram for differentiating complex from simple febrile seizures in children

Article Title: A nomogram integrating IL‑1β, IL‑6, and vitamin D for differentiating complex from simple febrile seizures

Article References: Xie, M., Shi, J., Zhang, Y., Yang, Y., & Zhao, L. (2026). A nomogram integrating IL‑1β, IL‑6, and vitamin D for differentiating complex from simple febrile seizures. BMC Pediatrics. https://doi.org/10.1186/s12887-026-07838-8

Image Credits: AI Generated

DOI: 10.1186/s12887-026-07838-8

Keywords: febrile seizures, IL-1β, IL-6, vitamin D, nomogram, pediatrics, biomarkers, risk prediction, inflammation, 25-hydroxyvitamin D, logistic regression, emergency medicine

The research focuses on a family of CD4-positive helper T cells known as Th17 cells, which have occupied an ambiguous position in cystic fibrosis immunology for over a decade. Elevated levels of interleukin-17, the signature cytokine of this lineage, were initially interpreted as a hallmark of pathology, since IL-17 drives neutrophil recruitment and tissue-destructive inflammation. Later work complicated that picture by showing that Th17 cells are functionally heterogeneous. Conventional Th17 cells, which co-produce IL-17 alongside the anti-inflammatory cytokine IL-10 and the epithelial-supporting IL-22, actually promote mucosal homeostasis and barrier integrity. By contrast, a distinct pro-inflammatory population, termed Th1/17 for its co-expression of interferon-gamma and IL-17 in the absence of IL-10, has been implicated in chronic inflammatory diseases ranging from multiple sclerosis to Crohn’s disease. Which of these faces Th17 presents in the cystic fibrosis lung remained an open question.

To resolve it, the team analysed T cells isolated from explanted lungs and blood of people with cystic fibrosis, alongside non-CF lung tissue and healthy donor blood. Using high-dimensional flow cytometry and unsupervised clustering based on chemokine receptor expression, they identified two pathogenic subsets, CCR5-positive Th1/17 cells and pro-inflammatory CCR5-positive Th17 cells, that were markedly enriched in cystic fibrosis lungs compared with both patient blood and non-CF lungs. Critically, this enrichment was not a general feature of the disease. The pathogenic subsets expanded selectively in lungs chronically colonized by Pseudomonas aeruginosa, irrespective of whether other pathogens such as Staphylococcus aureus were also present. In Pseudomonas-negative patients, protective conventional Th17 cells predominated instead, pointing to the bacterium itself as the upstream driver of the pathological shift.

The functional consequences of this shift were striking. In an air-liquid interface model of primary human bronchial epithelium, a laboratory system that recapitulates the differentiated, ciliated airway lining, activated Th1/17 and pro-inflammatory Th17 cells caused extensive disruption of epithelial integrity. Immunofluorescence staining for zonula occludens-1, a core component of tight junctions, revealed discontinuous, fragmented junctional patterns in cultures exposed to these subsets, while conventional Th17 cells left the barrier largely intact. Quantitative artificial intelligence-assisted image analysis confirmed the selective loss of junctional continuity. The pathogenic subsets also provoked a significantly stronger inflammatory response from epithelial cells, which released elevated amounts of cytokines and chemokines including IL-8, IL-6, CCL20 and RANTES, molecules that in turn recruit further immune cells to the airway wall.

Transcriptomic profiling by RNA sequencing deepened the picture. Pulmonary Th1/17 and pro-inflammatory Th17 cells from Pseudomonas-infected cystic fibrosis lungs displayed a distinctive signature of 210 upregulated and 40 downregulated genes compared with the same subsets in blood and non-CF lungs. Gene set enrichment analysis showed that lung-resident pathogenic cells upregulated 21 pathways linked to bacterial response, inflammation and tissue remodelling, with high-ranking genes including PPARG, CEBPD and IRAK2, transcriptional regulators known to shape Th17 differentiation and function. Peripheral counterparts of the same subsets showed a largely repressed programme, indicating that the lung environment itself actively reconfigures these cells rather than merely recruiting pre-formed effectors from the circulation.

T cell receptor sequencing added a crucial layer of evidence. The researchers found a significant expansion of private clonotypes, receptor sequences unique to individual patients, within cystic fibrosis lungs, accounting for 45.8 percent of the Th1/17 repertoire compared with roughly 22 percent in non-CF lungs. Among the most expanded clonotypes, some were shared between Th1/17 and pro-inflammatory Th17 cells but minimally represented in Th1 or conventional Th17 populations, suggesting a common antigenic experience driving functional convergence. Partial overlap between the receptor repertoires of pathogenic subsets and conventional Th17 cells, but not Th1 cells, provided a molecular fingerprint of lineage relationships that the team then tested experimentally.

That experimental work centred on dendritic cells, the antigen-presenting sentinels that instruct T cell fate. The team exposed human monocyte-derived dendritic cells to 26 clinical Pseudomonas aeruginosa strains isolated longitudinally from Danish cystic fibrosis patients, spanning early isolates taken at disease onset and late isolates collected after years of chronic colonization. Late strains were internalized more efficiently and persisted longer inside dendritic cells than the reference laboratory strain PAO1. More importantly, clinical isolates skewed the dendritic cell cytokine output toward a polarizing cocktail of IL-1β and IL-23, the two cytokines known to drive interferon-gamma-producing Th17 differentiation, while relatively suppressing IL-12, the canonical Th1-polarizing signal. IL-1β secretion correlated with intracellular bacterial persistence, and clinical strains also triggered strong release of CCL20, the chemokine that recruits CCR6-positive Th17 cells to sites of infection.

In antigen-specific co-culture assays, the researchers then demonstrated that conventional Th17 cells, not Th1 cells, are the precursors of the pathogenic populations. After ten days of co-culture with Pseudomonas-infected dendritic cells, sorted conventional Th17 cells acquired robust interferon-gamma and IL-17 co-expression, whereas Th1 cells never converted. Unexpectedly, early clinical isolates lacking the classic adaptations of chronic infection, such as reduced motility and biofilm formation, were at least as effective as late isolates at inducing this conversion, and some strains exceeded the levels seen with PAO1. The reprogramming extended to transcription factors: converted cells upregulated C/EBPδ and PPARγ, and in some cases BATF3, mirroring the profile of lung-resident pathogenic Th17 cells from patients. This indicates that the immunostimulatory virulence determinants responsible are present from the earliest stages of colonization and retained throughout bacterial adaptation to the cystic fibrosis lung.

The study thereby rewrites a long-standing paradigm. Adaptive immune dysfunction in cystic fibrosis was widely assumed to emerge only in late-stage disease, but the new data show that Pseudomonas aeruginosa can corrupt protective Th17 immunity from the moment it establishes infection, creating a self-sustaining immunopathological loop in which reprogrammed T cells damage the epithelium, epithelial cells release chemokines that recruit more Th17 cells, and the resulting inflammation further impairs bacterial clearance. The findings carry direct therapeutic implications. IL-1 receptor blockade with anakinra has already been shown to mitigate Pseudomonas-driven airway inflammation in cystic fibrosis, and IL-23 inhibitors are clinically established in other chronic inflammatory diseases, although safety concerns about prolonged IL-1β blockade and the need to preserve protective mucosal immunity remain. The authors caution that their lung cohort reflects advanced disease and that the specific bacterial or host antigens driving the T cell skewing are still unknown. Even so, selectively depleting Th1/17 and pro-inflammatory Th17 cells, or blocking their generation from conventional Th17 precursors, now stands as a credible precision immunomodulatory strategy, one that could address the inflammation that persists even in patients receiving CFTR modulator therapy.

Subject of Research: Pseudomonas aeruginosa-driven reprogramming of Th17 cells in cystic fibrosis lung immunopathology

Article Title: Pseudomonas aeruginosa induces the generation of pathogenic IFNγ+Th17 cells that promote lung damage and chronic inflammation in cystic fibrosis

Article References: Dusetti, I., Conte, G., Chiara, M., Puccio, S., Guidone, D., Ricciardelli, E., Cibella, J., Ronzio, M., Dolfini, D., Rossi, E., Landini, P., Ascagni, M., Orlandi, R., Damarco, F., Palleschi, A., Gramegna, A., Blasi, F., Lugli, E., Galietta, L. J., … Paroni, M. (2026). Pseudomonas aeruginosa induces the generation of pathogenic IFNγ+Th17 cells that promote lung damage and chronic inflammation in cystic fibrosis. Nature Microbiology. https://doi.org/10.1038/s41564-026-02469-2

Image Credits: AI Generated

DOI: 10.1038/s41564-026-02469-2

Keywords: cystic fibrosis, Pseudomonas aeruginosa, Th17 cells, interferon-gamma, dendritic cells, IL-23, IL-1β, epithelial barrier, T cell receptor, mucosal immunity, chronic inflammation, immunotherapy

L-carvone is a ketone monoterpene best known as the characteristic scent of spearmint, produced by plants of the Mentha genus. It exists as two mirror-image forms, or optical isomers, with the (R)-(−) form, known as L-carvone, and the (S)-(+) form, known as D-carvone, displaying distinct biological profiles. Previous research has attributed a remarkable range of activities to carvone, including antibacterial, antifungal, antioxidant, anti-neurodegenerative, vasorelaxant, and anticancer effects. Studies have also linked the compound to cardiovascular protection and atheroprotection through mechanisms such as reducing foam cell formation, modulating macrophage balance, and lowering oxidative stress. The new study, led by Guilherme Miniskiskosky and senior author Andréa Emilia Marques Stinghen at the Federal University of Paraná in Curitiba, is the first to test whether these properties extend to the specific inflammatory storm that uremia unleashes on blood vessel walls.

To create a realistic model of the uremic environment, the researchers recruited 14 patients with stable end-stage kidney disease undergoing hemodialysis at a single dialysis unit in Curitiba, Brazil. Participants had been on dialysis for at least three months, and the team carefully excluded anyone with active infection, cancer, autoimmune disease, liver dysfunction, severe mineral disturbances, or use of drugs such as glucocorticoids and immunosuppressants that could confound inflammatory measurements. Serum collected from all patients was pooled in equal amounts to create an averaged uremic milieu, minimizing the influence of any single patient’s biochemistry. The study was approved by the Ethics Committee of Pontifícia Universidade Católica do Paraná, and all patients provided signed informed consent.

The experimental system centered on EA.hy926 cells, a well-established human endothelial cell line, grown under standard conditions and exposed for 24 hours to one of three treatments: a 10 percent uremic serum pool, L-carvone at 100 micromolar, or the two combined. The carvone dose was chosen after a careful dose-response screen. At concentrations of 200 micromolar and above, the compound significantly reduced endothelial cell viability, but at 100 micromolar it left viability untouched, whether applied alone or alongside uremic serum. This established a safe working concentration for probing anti-inflammatory effects without cytotoxic confounders. The 24-hour exposure window was selected to allow sufficient time for transcriptional and inflammatory responses to unfold.

The results were striking. Uremic serum, as expected, drove up gene expression of the pro-inflammatory interleukins IL-6, IL-8, and IL-1β in the endothelial cells. When L-carvone was added, it significantly reduced IL-1β gene expression compared with uremic serum alone, a finding of particular importance because IL-1β sits near the top of the inflammatory cascade, amplifying vascular damage through activation of the nuclear factor kappa-B (NF-κB) pathway and contributing to arterial calcification. At the protein level, the effects broadened considerably. Carvone treatment significantly lowered production of IL-6, IL-8, and IL-1β, as well as tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor A (VEGF-A), and serum amyloid A (SAA), an acute-phase protein secreted by the liver that promotes pro-inflammatory and pro-thrombotic activity on vascular endothelial cells. Levels of the adhesion molecule ICAM-1 also fell substantially, from about 12.05 picograms per milliliter in uremic serum-treated cells to 6.25 picograms per milliliter when carvone was present.

Beyond quieting inflammatory signaling, the compound appeared to interfere with one of the most consequential steps in atherosclerosis: the recruitment of monocytes to the vessel wall. Endothelial cells exposed to uremic serum produce monocyte chemoattractant protein 1 (MCP-1), a chemical beacon that draws circulating monocytes toward the endothelium, where they can invade the vessel wall and seed atherosclerotic plaques. In the study, carvone significantly reduced MCP-1 production under uremic conditions. To test the functional consequence, the team used modified Boyden chambers, placing treated endothelial cell supernatant in the lower compartment and U-937 monocyte-like cells above a porous membrane. Supernatant from uremic serum-treated endothelial cells significantly increased monocyte migration, but supernatant from cells co-treated with carvone significantly reduced it, demonstrating that the anti-inflammatory effect translates into reduced leukocyte recruitment.

Perhaps the most visually compelling evidence came from scanning electron microscopy. Untreated control cells displayed the classic architecture of intact endothelium, spread flat across the substrate in a confluent monolayer. Cells exposed to uremic serum showed the hallmarks of uremic injury: an abundance of filopodia, loss of intercellular adhesions, rounded cell bodies, perforations in the plasma membrane, and scattered cellular debris. These morphological changes matter because uremic toxins are known to disrupt adherens and occluding junctions between endothelial cells, increasing vascular permeability and accelerating vascular damage. Remarkably, cells treated with uremic serum plus carvone largely reverted to a control-like pattern, remaining adhered and spread across the substrate. Carvone also promoted endothelial cell proliferation, which the authors suggest could support regeneration of an endothelial barrier damaged by toxin accumulation, although they caution that increased proliferation alone does not prove restored barrier function.

The authors are careful to frame these findings as mechanistic observations rather than a prescription. The 100 micromolar concentration used in vitro may exceed the circulating levels achievable in humans, since pharmacokinetic studies indicate that carvone is rapidly metabolized and cleared, and quantitative data on attainable plasma or tissue concentrations remain limited. Previous human studies have documented systemic exposure to carvone after oral intake of peppermint and caraway oil preparations and after topical exposure, but these do not establish clinical efficacy or safety of isolated carvone in CKD patients. The researchers also acknowledge that they did not directly measure NF-κB activation or antioxidant pathways, so the precise molecular mechanism behind the observed effects remains speculative, even though other experimental models have linked carvone’s anti-inflammatory actions to NF-κB inhibition.

Additional limitations shape how the results should be interpreted. The EA.hy926 cell line, while a standard tool, may not fully reproduce the behavior of primary human endothelial cells, and validation in primary cells is needed. The pooled serum from 14 patients smooths away inter-individual variability, so studies using serum from larger numbers of individual patients will be important to confirm that the effects hold across different clinical profiles. The authors also note that future work should explore carvone’s effects in other relevant cell types, such as vascular smooth muscle cells and renal tissue, and that in vivo studies will be essential to understand how the compound behaves in complex biological systems.

Even with those caveats, the study represents a genuine first. The researchers demonstrated for the first time that the dysfunctional, inflammatory profile that uremia imposes on endothelial cells can be attenuated by L-carvone treatment in vitro, with reductions in inflammatory biomarkers, reduced leukocyte recruitment, and reversal of uremia-induced structural damage. Because elevated levels of molecules like IL-6, TNF-α, and MCP-1 are linked to poorer cardiovascular prognosis, blunting their production could, in principle, translate into meaningful vascular protection for the CKD population. The work opens a new avenue for investigating how natural monoterpenes might be harnessed against uremic inflammation, and it provides a foundation for the animal studies and, eventually, clinical trials that would determine whether the spearmint molecule can move from the culture dish to the dialysis clinic.

Subject of Research: Anti-inflammatory effects of L-carvone on uremia-induced endothelial dysfunction in chronic kidney disease

Article Title: Potential anti-inflammatory effect of L-carvone in endothelial dysfunction triggered by uremia related to chronic kidney disease

Article References: Miniskiskosky, G., da Cunha, R. S., Gregório, P. C., Azevedo, C. A. B., Pereira, V. C., de Souza Ramos, E. A., & Stinghen, A. E. M. (2026). Potential anti-inflammatory effect of L-carvone in endothelial dysfunction triggered by uremia related to chronic kidney disease. Molecular Biology Reports, 53(1), Article 1651. https://doi.org/10.1007/s11033-026-12806-7

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12806-7

Keywords: chronic kidney disease, L-carvone, endothelial dysfunction, uremic toxins, inflammation, hemodialysis, monoterpene, cardiovascular disease, IL-1β, MCP-1, monocyte recruitment, natural compounds

The research team, led by Zhe Gao and Xin Zhang, set out to explore a question that has remained surprisingly open: what role, if any, does TRIM28 play in regulating the behavior of macrophages and the keratinocytes they communicate with? TRIM28, short for tripartite motif-containing 28, is a multifunctional protein best known for its involvement in transcriptional regulation and epigenetic modification. It can influence protein stability through ubiquitination and SUMOylation, two post-translational modifications that attach small protein tags to targets and alter their behavior. Despite growing interest in TRIM family proteins across immunology and cancer biology, TRIM28’s role in macrophage polarization had not been clearly defined.

To probe this question, the researchers used a well-established laboratory model. They cultured human THP-1 monocytic cells and differentiated them into macrophage-like cells using a chemical called phorbol 12-myristate 13-acetate. Separately, they maintained HaCaT keratinocytes, an immortalized human skin cell line. Using small interfering RNAs, they silenced TRIM28 expression in the macrophages, and in complementary experiments they boosted TRIM28 levels using an overexpression plasmid. These two approaches, gene knockdown and gene overexpression, allowed the team to observe what happens when TRIM28 is removed or amplified within the same cellular environment.

The results were striking. When TRIM28 was silenced, flow cytometry analysis revealed a marked shift in macrophage phenotype: the proportion of CD68-positive CD206-positive cells, associated with an M2-like or anti-inflammatory profile, increased to 25 percent from lower baseline levels. Conversely, the proportion of CD68-positive CD86-positive cells, associated with an M1-like or pro-inflammatory profile, dropped to just 5 percent. Enzyme-linked immunosorbent assays confirmed the functional consequences: silencing TRIM28 reduced secretion of the pro-inflammatory cytokines IL-6 and TNF-α while increasing the anti-inflammatory cytokine IL-10. Western blotting reinforced these findings, showing decreased expression of the M1-associated marker iNOS and increased expression of the M2-associated marker Arg1. When TRIM28 was overexpressed, every one of these trends reversed, pushing macrophages toward the pro-inflammatory state.

The team then traced the molecular pathway underlying this effect. Prior research had suggested that TRIM28 can stabilize NLRP3, a key component of the inflammasome, a multiprotein complex that triggers inflammatory signaling. NLRP3, in turn, is known to activate its downstream partner SGT1. In the current study, TRIM28 knockdown reduced the expression of both NLRP3 and SGT1, while overexpression raised their levels. Crucially, the researchers also examined functional readouts of inflammasome activation. TRIM28 knockdown decreased levels of cleaved caspase-1 and mature IL-1β, both hallmarks of inflammasome activity, and reduced secretion of IL-1β into the culture medium. Overexpression produced the opposite pattern. Co-immunoprecipitation experiments further revealed that TRIM28 physically interacts with NLRP3 and that TRIM28 overexpression significantly increased the SUMOylation of NLRP3, a modification previously linked to inflammasome stabilization.

With the macrophage-side mechanism established, the investigators turned to the keratinocyte side of the equation. They placed modified macrophages in the upper chamber of a Transwell system, separated by a porous membrane from HaCaT keratinocytes below, allowing soluble factors to pass but preventing direct cell contact. After 24 hours of co-culture, they measured keratinocyte viability and invasive capacity. The differences were dramatic. Co-culture with TRIM28-silenced macrophages reduced HaCaT cell viability to 60 percent of control levels, while co-culture with TRIM28-overexpressing macrophages raised viability to 140 percent. Invasion assays showed a similar pattern: silencing TRIM28 in macrophages reduced keratinocyte invasion to 60 percent of baseline, whereas overexpression increased it to 180 percent. These cellular behaviors, hyperproliferation and invasion, are relevant to inflammatory skin responses, although the authors are careful to note that they do not by themselves demonstrate a role for TRIM28 in psoriasis in living organisms.

To confirm that the NLRP3/SGT1 axis and SUMOylation were genuinely required for these effects rather than incidental, the researchers performed a series of rescue experiments. They knocked down NLRP3 or SGT1 in macrophages overexpressing TRIM28, or treated the cells with 2-D08, a chemical inhibitor of SUMOylation. Each intervention partially reversed the TRIM28-driven shift toward the pro-inflammatory macrophage phenotype, restoring the balance of CD86-positive and CD206-positive populations. The interventions also normalized cytokine secretion patterns, reduced cleaved caspase-1 and mature IL-1β levels, and attenuated the enhanced NLRP3 SUMOylation. Most importantly, these same interventions partially reversed the proliferative and invasive changes observed in co-cultured keratinocytes, confirming that the NLRP3/SGT1 pathway and SUMOylation are functionally required for the macrophage-mediated effects on skin cells.

The study places TRIM28 within a growing family of TRIM proteins implicated in inflammatory skin biology. Previous work has shown that TRIM14 promotes psoriasis-like inflammation by activating NF-κB signaling, and that TRIM27 amplifies IL-6/STAT3 signaling in keratinocytes. The current research extends this picture by suggesting that TRIM28 operates through a distinct mechanism, one involving post-translational modification of the NLRP3 inflammasome rather than transcriptional regulation alone. This positions TRIM28 as a potential bridging molecule between the epigenetic machinery of the cell and the innate immune response, a role that has parallels in other inflammatory conditions. The researchers draw comparisons to the HSP90β-SGT1 complex, which stabilizes NLRP3 in autoinflammatory syndromes, and to studies in fatty liver disease where HSP90 inhibition suppresses NLRP3 activation.

Nevertheless, the authors are emphatic about the limitations of their work. All experiments were performed in simplified in vitro systems using immortalized cell lines, which cannot fully replicate the cellular diversity, tissue architecture, and immune microenvironment of human psoriatic skin. The team did not examine TRIM28 expression in actual psoriatic lesions, did not analyze patient-derived samples, and did not correlate TRIM28 levels with disease severity. Macrophage polarization was assessed using a limited marker panel, and the authors acknowledge that the M1/M2 framework is a simplified operational model rather than a definitive classification of macrophage states. More comprehensive approaches, including single-cell RNA sequencing and multiplex flow cytometry, would be needed to fully characterize the macrophage phenotypes regulated by TRIM28. Additionally, the specific enzyme responsible for NLRP3 SUMOylation in this context remains unknown, as TRIM28 itself lacks SUMO ligase activity, suggesting intermediary proteins may be involved.

Looking forward, the researchers outline several priorities for future investigation. They propose examining TRIM28 expression and localization in human psoriatic tissue alongside clinical markers, validating the TRIM28–NLRP3/SGT1 axis in patient-derived cells and three-dimensional organotypic skin cultures, and testing whether modulating TRIM28 alters inflammation in animal models of psoriasis-like dermatitis. They also call for a more precise mapping of the molecular interactions between TRIM28, NLRP3, and SGT1, including identification of the relevant SUMO E3 ligase and assessment of downstream inflammasome assembly events. Until such work is completed, the current study stands as a rigorous piece of mechanistic cell biology, defining a TRIM28-dependent inflammatory pathway in a controlled laboratory setting. Its contribution is foundational rather than translational: it illuminates how a single regulatory protein can reshape the inflammatory conversation between two cell types central to skin immunity, while leaving open the critical question of whether that conversation drives human disease.

Subject of Research: TRIM28 regulation of macrophage polarization and keratinocyte behavior via the NLRP3/SGT1 axis in vitro

Article Title: TRIM28 Promotes Keratinocyte Proliferation and Invasion by Activating NLRP3/SGT1 Axis‐Mediated Macrophage Pro‐Inflammatory Polarization in an In Vitro Macrophage–Keratinocyte Co‐Culture Model

Article References: Gao, Z., Zhang, X., Wang, J., & Yang, N. (2026). TRIM28 Promotes Keratinocyte Proliferation and Invasion by Activating NLRP3/SGT1 Axis‐Mediated Macrophage Pro‐Inflammatory Polarization in an In Vitro Macrophage–Keratinocyte Co‐Culture Model. Immunity, Inflammation and Disease, 14(9), Article e70522. https://doi.org/10.1002/iid3.70522

Image Credits: AI Generated

DOI: 10.1002/iid3.70522

Keywords: TRIM28, macrophage polarization, NLRP3 inflammasome, SGT1, SUMOylation, keratinocytes, psoriasis, inflammation, IL-1β, co-culture, innate immunity, skin biology

Non-tuberculous mycobacteria, often abbreviated NTM, are environmental organisms that increasingly cause chronic and debilitating lung disease worldwide. Among them, Mycobacterium abscessus stands out as particularly menacing. It is naturally resistant to many standard antibiotics, it can form ropelike cords that shield it from engulfment by immune cells, and it thrives in patients with pre-existing lung damage such as bronchiectasis, cystic fibrosis, or pulmonary fibrosis. Treatment regimens typically stretch for many months, involve multiple toxic drugs, and frequently fail to eradicate the infection. Against this grim clinical backdrop, the question of how the immune system naturally fights M. abscessus has remained surprisingly underexplored, particularly with respect to γδ T cells, an unconventional lymphocyte population whose role in NTM infection had never been systematically characterized.

γδ T cells differ from the conventional αβ T cells that dominate textbook immunology. Rather than recognizing peptide fragments presented by major histocompatibility molecules, they respond rapidly to a wide range of stress signals and microbial products, earning them a reputation as a bridge between innate and adaptive immunity. A major subset of these cells produces interleukin-17A, a powerful inflammatory cytokine best known for recruiting neutrophils and shaping defenses at body surfaces. To determine whether these cells matter in M. abscessus infection, the researchers built a mouse model of pulmonary infection and mapped the immune landscape of lung tissue over the early days of disease using single-cell RNA sequencing, a technique that captures the gene expression profile of thousands of individual cells simultaneously.

The single-cell atlas revealed a striking pattern. As infection took hold, γδ T cells accumulated in the lung and expanded a population that expressed high levels of IL-17A. When the team removed γδ T cells entirely, using mice genetically engineered to lack them, the consequences were dramatic: bacteria persisted at far higher levels in the lungs and spleens, and lung inflammation worsened. Conversely, when γδ T cells were depleted in animals that had already cleared a first infection and were then re-challenged, the protective advantage of prior exposure evaporated. These experiments established γδ T cells as indispensable players in the early defense against M. abscessus, a finding that had not been demonstrated before for any non-tuberculous mycobacterial pathogen.

Delving deeper, the investigators identified IL-17A itself as the linchpin of this protective response. Mice unable to produce IL-17A lost much of their capacity to control the infection, and importantly, the defect traced back to the γδ T cells themselves. Without IL-17A signaling, the cells became less adept at recognizing the bacterium and lost much of their cytotoxic firepower. In an elegant series of transfer experiments, IL-17A-deficient γδ T cells failed to protect infected animals, whereas their normal counterparts succeeded. This revealed something unusual: IL-17A was not merely acting as a broadcast signal to other immune players but was required within the γδ T cells themselves, a cell-intrinsic requirement that underscores how tightly the cytokine and its producer are wired together during this infection.

The mechanism by which these cells actually kill the bacterium proved to be equally instructive. M. abscessus is an extracellular pathogen during key phases of infection, residing outside host cells in the airways and tissue spaces. The researchers found that IL-17A-positive γδ T cells eliminated extracellular bacteria through a granzyme B-dependent cytotoxic pathway. Granzyme B is a serine protease classically associated with the destruction of virus-infected or malignant cells, delivered through pore-forming perforin or other release mechanisms. Its deployment against free-living bacteria adds a new dimension to the antimicrobial portfolio of γδ T cells and explains how a lymphocyte population usually discussed in the context of autoimmunity and inflammation can act as a direct bactericidal weapon.

How, then, does the immune system know to mobilize these cells in the first place? The answer lies in a cascade that begins with Toll-like receptor 2, a pattern-recognition receptor on macrophages that detects components of the bacterial cell wall. When M. abscessus engaged TLR2 on lung macrophages, the macrophages responded by secreting two cytokines, interleukin-1β and interleukin-23. This cytokine pair is a well-known stimulus for IL-17 production in T cells, and in this context it drove both the expansion and the activation of the IL-17A-positive γδ T cell population. Blocking either IL-1β or IL-23 in infected mice diminished the γδ T cell response and impaired bacterial control, mapping out a complete signaling axis that runs from bacterial recognition through macrophage activation to lymphocyte mobilization and, ultimately, bacterial killing.

Perhaps the most clinically resonant aspect of the study concerns patients whose immunity depends on interferon-gamma, the canonical cytokine for defense against mycobacteria. A subset of individuals, particularly in Southeast Asia, develops autoantibodies that neutralize their own interferon-gamma, leaving them exquisitely vulnerable to disseminated NTM infections. Using single-cell RNA sequencing of peripheral blood cells from NTM patients, the researchers found evidence that anti-interferon-gamma autoantibodies compromise γδ T cell function in humans, mirroring what they observed in mice lacking the interferon-gamma receptor. Crucially, in mice engineered without functional interferon-gamma signaling, IL-17A-positive γδ T cells still conferred protection, and the same held true in a model combining M. abscessus infection with bleomycin-induced pulmonary fibrosis. In other words, this arm of immunity operates independently of the interferon-gamma axis and remains effective even in scarred, damaged lungs.

The implications for therapy are considerable. Current treatment of NTM disease relies almost entirely on antibiotics that the pathogen is adept at resisting, and there are no licensed immunotherapies that bolster host defenses. If the pathways defined in this study can be harnessed in patients, whether by stimulating IL-1β and IL-23 signaling, expanding protective γδ T cell populations, or delivering IL-17A-driven cytotoxic activity directly, clinicians could gain a means of strengthening the lung’s own antimicrobial machinery. Such approaches would be especially valuable for the growing population of patients with anti-interferon-gamma autoantibodies or structural lung disease, for whom conventional regimens offer diminishing returns. The researchers caution that translating mouse findings to the clinic will require careful work, particularly because IL-17A is also implicated in inflammatory conditions such as psoriasis and could carry safety risks if induced systemically. Nevertheless, the identification of a concrete, mechanistically defined cell type that can clear M. abscessus marks a genuine advance. It transforms γδ T cells from immunological bystanders into a promising therapeutic target, and it reframes the fight against antibiotic-resistant mycobacteria as a battle that the immune system, with the right encouragement, may be able to win on its own terms.

Subject of Research: The role of IL-17A-producing γδ T cells in controlling pulmonary Mycobacterium abscessus infection in mice.

Article Title: IL-17A-producing γδ T cells control pulmonary Mycobacterium abscessus infection in mice

Article References: Hu, X., Lin, S., Meng, W., Liu, H., Qin, Z., Wu, Z., Wan, Y., Ma, S., Yang, X., Yin, Z., Chu, Y., Zhang, W., Shao, L., & Lin, Y. (2026). IL-17A-producing γδ T cells control pulmonary Mycobacterium abscessus infection in mice. Nature Microbiology. https://doi.org/10.1038/s41564-026-02466-5

Image Credits: AI Generated

DOI: 10.1038/s41564-026-02466-5

Keywords: Mycobacterium abscessus, non-tuberculous mycobacteria, γδ T cells, IL-17A, interferon-gamma, granzyme B, TLR2, IL-1β, IL-23, pulmonary infection, immunology, antibiotic resistance