The study, reported in Frontiers in Psychiatry, enrolled consecutive patients admitted to Northern Hospital of Sinopharm Group in China from June 2020 through December 2021. Participants were 18 years or older but were required to be between 45 and 80 for inclusion, and each had a clinical diagnosis of acute ischemic stroke supported by neurological symptoms, physical examination and neuroimaging. Only mild-to-moderate strokes were included, defined by an admission NIHSS score of no more than 15. Patients with severe stroke, impaired consciousness, pre-existing anxiety disorders, several major vascular or psychiatric conditions, substance dependence, or medications that could exacerbate anxiety were excluded.

Neurological severity was measured with the 15-item NIHSS, which ranges from 0 to 42 and evaluates domains including consciousness, eye movements, visual fields, facial movement, limb strength, sensation, coordination, speech and language. Higher scores represent greater impairment. Anxiety was assessed with the 7-item Generalized Anxiety Disorder scale, or GAD-7, covering symptoms during the preceding two weeks. The researchers divided participants into a lower-anxiety group with a score of 4 or less and a higher-anxiety group with a score above 4, equivalent to 5 or more. GAD-7 is a symptom-severity screen rather than a stand-alone diagnostic interview for an anxiety disorder.

Peripheral blood was collected on hospital admission, and serum was separated and stored at minus 80 degrees Celsius until analysis. Using enzyme-linked immunosorbent assays, investigators measured three CC chemokines: monocyte chemoattractant protein-1, MCP-1; MIP-1α; and macrophage inflammatory protein-1β, MIP-1β. Laboratory personnel were blinded to participants’ clinical and demographic characteristics. MIP-1α was selected for focused moderation analysis because initial correlation screening showed that its association with NIHSS scores differed markedly between anxiety groups, making the subsequent analysis exploratory and hypothesis-generating rather than a prespecified primary test.

Descriptive comparisons divided the cohort into four subgroups based on anxiety and MIP-1α concentration, with MIP-1α separated at the median within each anxiety group. NIHSS scores differed across these groups, with the lower-anxiety, higher-MIP-1α subgroup having a mean score of 0.35, compared with 1.32 in the lower-anxiety, lower-MIP-1α group; means were 1.24 and 1.54 in the higher-anxiety groups with higher and lower MIP-1α, respectively. The lower-anxiety, higher-MIP-1α group also had significantly lower scores than each of the other three groups after Holm-adjusted post-hoc comparisons. Sex distribution differed across the groups, but age, smoking, alcohol consumption, hypertension and diabetes did not differ significantly.

Spearman correlations showed that MIP-1α had opposite directional relationships with NIHSS scores in the two anxiety strata: the association was significantly negative among participants with GAD-7 scores of 4 or less but became positive in those scoring above 4. By contrast, MCP-1 and MIP-1β were positively correlated with neurological impairment in both anxiety groups. MIP-1α was also strongly positively correlated with MCP-1 and MIP-1β in both strata, all with p values below 0.001. These patterns linked the MIP-1α result to a broader chemokine profile, although the study did not directly test how the three markers mediate one another.

Hierarchical linear regression was used to test whether anxiety group moderated the MIP-1α–NIHSS association. Model 1 adjusted for age, sex, smoking, alcohol consumption, hypertension and diabetes. Model 2 added MIP-1α and anxiety group, and Model 3 added the MIP-1α-by-anxiety interaction. The interaction was significant, with a standardized beta of 0.16 and p = 0.006, while MIP-1α alone remained inversely associated with NIHSS scores at beta = minus 0.19 and p = 0.001. The adjusted R-squared increased from 0.10 in Model 2 to 0.13 in Model 3. Simple-slope analysis found a significant inverse MIP-1α association in the lower-anxiety group, with beta = minus 0.32 and p below 0.001, but no association in the higher-anxiety group, where beta was minus 0.003 and p was 0.969. Thus, the study’s detailed results do not support every directional claim in its abstract: the highest-anxiety stratum did not show a significant positive simple slope, even though the formal interaction was significant.

Receiver operating characteristic analysis assessed how well the models distinguished patients with no NIHSS-detectable deficit from those with at least one point. The area under the ROC curve was 0.67 for Model 1, 0.74 for Model 2 and 0.76 for Model 3. Model 2 significantly outperformed Model 1, and Model 3 also significantly outperformed Model 1, with p below 0.001 for the latter comparison. However, Model 3 did not significantly outperform Model 2: the AUC difference was 0.02, and DeLong’s test returned p = 0.14. The interaction therefore strengthened the model’s fit, but it did not add a statistically demonstrable improvement in discrimination beyond the separate contributions of anxiety and MIP-1α.

Several design features limit interpretation. The cross-sectional assessment cannot establish whether inflammation preceded anxiety, whether anxiety amplified inflammation, whether severe stroke produced both, or whether another factor influenced all three. It also cannot demonstrate that managing anxiety would change MIP-1α signaling or neurological recovery. The single-center sample was restricted to mild-to-moderate ischemic stroke and had a median NIHSS score of 1, limiting applicability to severe or hemorrhagic stroke. Anxiety was self-reported without a structured diagnostic interview, MIP-1α was measured only once, and important clinical variables—including onset-to-assessment interval, reperfusion treatment, infarct location and volume, stroke subtype, previous stroke, medication use and social support—were not recorded. The inverse association between age and NIHSS may likewise reflect selection or restricted score range rather than a protective effect of older age.

Taken together, the study provides cross-sectional clinical evidence that post-stroke anxiety symptom severity can alter the statistical relationship between MIP-1α and acute neurological impairment. Its strongest support is for a statistically detectable interaction, not for a causal pathway or a clinically validated prediction tool. The AUC result reinforces that caution: adding the interaction improved model fit, but did not significantly improve discrimination over a model already containing anxiety group and MIP-1α. Prospective studies with serial symptom and biomarker measurements, larger and more diverse stroke populations, and direct testing of the proposed stress and blood–brain-barrier mechanisms would be required to determine whether the relationship holds over time and whether it has practical value outside this selected cohort.

Subject of Research: Cross-sectional study of post-stroke anxiety, MIP-1α and acute ischemic stroke severity

Article Title: Post-stroke anxiety symptoms moderate the predictive efficacy of MIP1-α on acute ischemic stroke severity

Article References: Li, M., Chen, T., Wang, Y., Zhou, M., Zhou, X., Xing, L., Huang, H., Zhou, P., Liao, Z., Chang, Y., Hu, X., Luo, X., Chen, Y.-H., Chen, L., Liu, Y., Wang, W., Wang, F., & Jiang, H. (2026). Post-stroke anxiety symptoms moderate the predictive efficacy of MIP1-α on acute ischemic stroke severity. Frontiers in Psychiatry, 17, Article 1785971. https://doi.org/10.3389/fpsyt.2026.1785971

Image Credits: AI Generated

DOI: 10.3389/fpsyt.2026.1785971

Keywords: ischemic stroke, post-stroke anxiety, MIP-1α, neuroinflammation, NIHSS, GAD-7, chemokines, blood biomarkers, psychoneuroimmunology, Post-stroke, anxiety, symptoms

The research team, led by investigators including Deep Goswami and Mitali Chatterjee, analyzed skin biopsies and blood plasma from PKDL patients and compared them with samples from healthy controls. Using immunohistochemistry and immunofluorescence, they quantified the populations of immune cells infiltrating the lesions, including CD8-positive T cells, CD68-positive macrophages, CD20-positive B cells, and CD66b-positive neutrophils. In parallel, they measured the levels of chemokines and cytokines circulating in the plasma using multiplex assays and ELISA, and examined the integrity of key structural proteins in the skin, such as E-cadherin, intercellular adhesion molecule-1, fibronectin, collagen types I and IV, and laminin.

What they found was a coordinated immune invasion. PKDL lesions were densely infiltrated with immune cells, and the hierarchy was clear: monocytes and macrophages dominated, followed by CD8-positive T cells, then neutrophils, and finally B cells. This was not a random accumulation but a targeted recruitment. The researchers detected elevated levels of specific chemokines in the circulation, including CCL2, CCL3, CCL4, CCL5, CXCL9, CXCL10, and IL-8, and these chemokines positively correlated with the abundance of their corresponding immune cell populations in the tissue. In other words, the chemical signals in the blood were acting as homing beacons, drawing each immune cell type into the skin lesions where they accumulated.

The structural consequences of this infiltration were equally striking. E-cadherin, a molecule that glues keratinocytes together and helps maintain the integrity of the epidermis, was significantly downregulated in the lesions, with the most pronounced reduction seen in macular lesions, the flat, pale patches characteristic of the disease. Meanwhile, intercellular adhesion molecule-1, or ICAM-1, was elevated, reflecting the inflammatory activation of the tissue. The extracellular matrix, the protein scaffold that gives skin its shape and resilience, was also significantly depleted, with reduced levels of fibronectin, collagen I, collagen IV, and laminin across both macular and polymorphic forms of PKDL.

Critically, the loss of these structural components was not independent of the immune invasion. The researchers found that the depletion of extracellular matrix proteins correlated inversely with the degree of immune cell infiltration, meaning that the more immune cells crowded into a lesion, the more the underlying scaffold was eroded. This inverse relationship suggests that the immune cells, or the inflammatory molecules they produce, are actively breaking down the tissue architecture rather than simply occupying space left behind by other processes.

To identify the molecular culprits, the team turned to the enzymes and cytokines known to degrade structural proteins. Matrix metalloproteinase 9, or MMP9, an enzyme capable of cleaving collagen and other matrix components, was elevated in the lesions. So were the pro-inflammatory cytokines TNF-alpha and IFN-gamma. Importantly, the levels of these molecules correlated inversely with E-cadherin and the extracellular matrix proteins, providing a plausible mechanism: the inflammatory milieu, rich in TNF-alpha, IFN-gamma, and MMP9, drives the breakdown of the adhesion molecules and structural proteins that hold the skin together.

The systemic picture reinforced the local one. In the plasma of PKDL patients, pro-inflammatory cytokines including TNF-alpha, IFN-gamma, IL-6, and IL-1beta were elevated, along with IL-4, a cytokine more typically associated with allergic and humoral immune responses. This combination suggests that PKDL is not a purely Th1 or Th2 inflammatory state but a mixed immune environment in which multiple signaling pathways converge on the skin. The elevated circulating chemokines, which correlated with tissue infiltration, further support the idea that the blood is carrying the instructions for immune cell homing to the lesions.

The clinical significance of these findings lies in their potential to explain the most visible and stigmatizing feature of PKDL: hypopigmentation. The researchers propose that the loss of E-cadherin and extracellular matrix components, driven by MMP9, TNF-alpha, and IFN-gamma, could cause a site-specific loss of melanocytes, the pigment-producing cells of the skin. If the structural framework that supports melanocytes is dismantled, those cells may be lost or dysfunctionally displaced, resulting in the pale patches that characterize macular PKDL. This mechanism links the immune pathology directly to the visible symptom, a connection that had remained poorly defined until now.

Beyond the mechanistic insight, the study has implications for how PKDL might be monitored and treated. The correlation between circulating chemokines and tissue infiltration suggests that blood markers could serve as non-invasive indicators of disease activity, potentially reducing the need for repeated skin biopsies. The identification of TNF-alpha, IFN-gamma, and MMP9 as central drivers of tissue remodeling also points to potential therapeutic targets. If the enzymatic and cytokine-mediated breakdown of E-cadherin and the extracellular matrix can be modulated, it may be possible to preserve skin architecture and prevent or reverse the hypopigmentation that causes so much social and psychological burden for patients.

PKDL remains a significant public health challenge in regions where visceral leishmaniasis is endemic, particularly in the Indian subcontinent and East Africa. Because PKDL patients can harbor parasites in their skin, they are thought to act as reservoirs that sustain transmission even after large-scale treatment campaigns have reduced visceral disease. Understanding the immune-mediated remodeling of skin architecture in PKDL therefore serves a dual purpose: it illuminates the biology of a neglected disease and may contribute to strategies aimed at interrupting the transmission cycle. By revealing how chemokine-driven immune infiltration, cytokine-mediated inflammation, and matrix-degrading enzymes converge to dismantle the skin’s structural integrity, this study provides a foundation for developing interventions that could improve both the clinical management and the epidemiological control of this disfiguring sequela of kala-azar.

Subject of Research: Immune-mediated tissue remodeling and hypopigmentation in Post-Kala-Azar Dermal Leishmaniasis

Article Title: Immune-mediated remodelling of tissue architecture in Post-Kala-Azar Dermal Leishmaniasis (PKDL)

Article References: Goswami, D., Saha, S., Roy, M., Mohammad, E., Maji, R., Sengupta, R., Sengupta, S., Roy, S., Chaudhuri, S. J., Das, N. K., Chakraborty, B., Chatterjee, U., & Chatterjee, M. (2026). Immune-mediated remodelling of tissue architecture in Post-Kala-Azar Dermal Leishmaniasis (PKDL). PLOS Neglected Tropical Diseases, 20(10), e0014798. https://doi.org/10.1371/journal.pntd.0014798

Image Credits: AI Generated

DOI: 10.1371/journal.pntd.0014798

Keywords: PKDL, visceral leishmaniasis, hypopigmentation, E-cadherin, MMP9, chemokines, extracellular matrix, macrophages, CD8 T cells, TNF-alpha, IFN-gamma, skin pathology

The review, authored by Lingling Mei, Zhihua Feng, Lizhu Chen, Weiwei Huang, and Yangkun Shen, with contributions from researchers at Fujian Normal University, Fuzhou Hospital of Traditional Chinese Medicine, and Fujian Cancer Hospital, proposes a unifying framework it calls paracrine network-driven niche evolution. Paracrine signaling is the process by which cells release molecules that act on nearby neighbors rather than traveling through the bloodstream to distant targets. In a tumor, this local messaging system links malignant cells to immune cells, fibroblasts, endothelial cells lining blood vessels, and other stromal residents. The authors contend that the hallmark features of triple-negative breast cancer—its heterogeneity, its early metastasis, and its frequent resistance to therapy—are emergent properties of these networks rather than fixed traits of individual tumor cells.

What makes this framework timely is the arrival of single-cell and spatial omics technologies. Traditional bulk sequencing averages out the identities of thousands of cells, obscuring the fact that a tumor is not a uniform mass but a patchwork of spatially organized neighborhoods. Single-cell RNA sequencing can now profile gene expression in individual cells, while spatial transcriptomics maps where those cells sit relative to one another. Applied to triple-negative breast cancer, these tools reveal that tumors are organized into distinct cellular niches, each maintained by its own repertoire of signaling molecules. Cancer cells at the invasive edge may be bathed in different signals than those near necrotic cores, and each niche can harbor cells with distinct vulnerabilities and distinct capacities for survival under treatment pressure.

Two principal communication modalities sustain these niches. The first is the release of soluble factors: cytokines, chemokines, growth factors, and metabolites that diffuse through the extracellular space and bind receptors on neighboring cells. The second is the exchange of extracellular vesicles, tiny membrane-bound packages that carry proteins, lipids, and nucleic acids from one cell to another. Unlike soluble factors, vesicles can deliver a coordinated cargo—microRNAs, messenger RNAs, and signaling proteins in a single package—effectively reprogramming the recipient cell. The review emphasizes that these two modes are not independent; they reinforce one another in feedback loops that can amplify a signaling state once it is established, locking parts of the tumor into aggressive behavioral patterns.

One of the most consequential ideas in the review is that therapy itself reshapes these communication networks. Chemotherapy is designed to kill dividing cells, but it also triggers stressed tumor cells and stromal cells to release new cocktails of signals. Damaged cells may secrete damage-associated molecular patterns that summon and polarize immune cells, sometimes in ways that blunt the immune response rather than enhance it. Surviving tumor cells may upregulate survival pathways in response to signals from cancer-associated fibroblasts. The result is therapy-induced rewiring: the paracrine network that existed before treatment is not the same network that exists after it. This dynamic remodeling helps explain why resistance so often emerges not through a single mutation but through a coordinated shift in the tumor’s social environment, and why the microenvironment can retain a kind of memory of prior treatment, priming it for faster adaptation upon relapse.

The consequences of this rewiring extend across every axis of tumor behavior. Tumor-cell plasticity—the capacity of cancer cells to switch states, for example from epithelial to mesenchymal-like phenotypes—is promoted by paracrine cues from the niche, endowing cells with motility and survival traits that support metastatic competence. Immune dysfunction is likewise a network phenomenon: signals such as certain chemokines recruit immunosuppressive myeloid cells and regulatory T cells into the tumor, while others exclude cytotoxic lymphocytes from critical regions, undermining both natural immune surveillance and immunotherapies such as immune checkpoint inhibitors. Vascular and metabolic remodeling, too, are driven by local signaling, as tumor cells and stromal cells induce abnormal vessel growth and reshape nutrient and oxygen availability, creating gradients that further diversify the niches within a single tumor.

Crucially, the review does not stop at diagnosis of the problem; it surveys therapeutic strategies aimed at interrupting pathological communication. These include blocking cytokine and chemokine signaling pathways, targeting stromal cells such as cancer-associated fibroblasts that nurture tumor cells, normalizing tumor vasculature to improve drug delivery and oxygenation, and intercepting extracellular vesicles or their cargo before they can reprogram recipient cells. The authors also discuss approaches that combine these interventions with existing chemotherapy and immunotherapy, on the logic that dismantling a tumor’s communication infrastructure may render the remaining cancer cells more vulnerable to conventional agents. Each strategy, however, depends on identifying which communication dependencies dominate in a given patient’s tumor—a task that requires better biomarkers and functional validation than currently exist.

Indeed, the review is candid about the obstacles standing between this framework and the clinic. Many paracrine pathways are redundant: blocking one signal may simply redirect traffic through another. Some communication molecules play protective roles in healthy tissue, raising the specter of toxicity when they are systemically inhibited. Extracellular vesicles are technically challenging to characterize and track in patients, complicating both biomarker development and drug targeting. Functional validation—demonstrating in rigorous models that a given network dependency is truly required for tumor survival—remains uneven across the field. The authors argue that overcoming these challenges will require integrating spatially resolved molecular data with functional assays and carefully designed clinical trials, so that combination therapies can be guided by biomarkers that reveal which communication circuits a tumor actually depends upon.

The conceptual shift the review advocates is subtle but potentially transformative. For decades, cancer research has focused on cell-intrinsic events: mutations, copy-number changes, and epigenetic alterations within the tumor cell. Those remain important, but the paracrine network framework insists that they are only half the story. Progression and treatment failure, in this view, are emergent consequences of spatially organized and temporally rewired signaling communities—properties that cannot be predicted by sequencing the cancer genome alone. If the framework holds up under experimental scrutiny, it points toward a future in which a patient’s tumor is mapped not just for its mutations but for its communication architecture, and therapy is designed to collapse the specific signaling dependencies that keep that architecture alive. For a disease as heterogeneous and relentless as triple-negative breast cancer, targeting the conversation rather than only the cells having it may prove to be the strategic breakthrough that has so far remained out of reach.

Subject of Research: Paracrine signaling networks in the tumor microenvironment of triple-negative breast cancer

Article Title: Paracrine networks driving heterogeneity and therapy resistance in triple-negative breast cancer

Article References: Mei, L., Feng, Z., Chen, L., Huang, W., & Shen, Y. (2026). Paracrine networks driving heterogeneity and therapy resistance in triple-negative breast cancer. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09077-y

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09077-y

Keywords: triple-negative breast cancer, tumor microenvironment, paracrine signaling, extracellular vesicles, cytokines, chemokines, cancer-associated fibroblasts, therapy resistance, tumor heterogeneity, single-cell omics, spatial transcriptomics, immunotherapy

The science behind IMM60 begins with a molecule that has fascinated immunologists for decades. Alpha-galactosylceramide, a lipid originally isolated from a marine sponge, is the archetypal activator of iNKT cells. These cells occupy a peculiar niche in the immune system: they carry an invariant T cell receptor, a fixed molecular sensor that recognizes lipid fragments displayed by a specialized presenting molecule called CD1d. When the right lipid locks into CD1d and engages the iNKT cell receptor, the result is a rapid, coordinated burst of immune activity. Unlike conventional T cells, which need weeks to expand and specialize against a new threat, iNKT cells respond within hours, releasing signaling proteins that recruit and energize other immune players, including cells that kill tumors directly.

Alpha-galactosylceramide itself, however, has proved awkward as a drug. It is chemically unstable, difficult to formulate, and its potency fades during storage and in the bloodstream. IMM60 was engineered to be a more robust cousin: a synthetic lipid agonist with enhanced potency and stability, encapsulated within liposomes to protect it from degradation and deliver it efficiently to the CD1d presentation machinery. The idea is that a stable, liposomal formulation could finally translate the dramatic immune activation seen in laboratory studies into a therapy that works reliably in patients, potentially priming tumors for attack by the immune system and working hand in hand with existing immunotherapies.

The IMP-MEL trial enrolled fifteen patients with advanced melanoma or non-small cell lung cancer, and fourteen of them received treatment, six with melanoma and eight with lung cancer. Together they received sixty-six infusions of liposomal IMM60, with a median of five infusions per patient and a range of two to six. Some patients received the drug on its own, while others received it in combination with pembrolizumab, an antibody that blocks the PD-1 checkpoint and is already a mainstay of immunotherapy for both tumor types. The combination strategy rests on a simple logic: IMM60 sounds the immune alarm, while pembrolizumab removes the molecular brakes that tumors use to silence the responding cells.

Safety was the trial’s central question, and the answer was reassuring. No dose-limiting toxicities were observed at any of the doses tested, and the study did not need to define a maximum tolerated dose, the ceiling that phase I trials exist to find. Treatment-related adverse events did occur, affecting ten of the fourteen treated patients, or seventy-one percent, but every one of them was graded as mild or moderate, meaning grade one or two on the standard toxicity scale, and all were self-limiting. For a drug designed to deliberately provoke the immune system, the absence of severe inflammatory side effects is a notable achievement, since excessive immune activation has derailed many immunotherapy candidates before them.

The pharmacokinetic data, which track how the drug moves through the body, showed clean, predictable behavior. Exposure increased in proportion to dose, with the maximum plasma concentration showing a strong linear fit across dose levels, and the drug lingered in circulation with a mean residence time of about seven hours. That predictability matters enormously for a first-in-human agent, because it means clinicians can anticipate how the body will handle each dose rather than contending with erratic spikes or unexpected accumulation. The liposomal delivery appears to have tamed a molecule that, in its earlier form, was notoriously difficult to manage pharmacologically.

More important than how the drug circulated was whether it engaged its biological target, and here the trial provided direct molecular evidence. Within twenty-four hours of infusion, the researchers observed downregulation of the iNKT cell T cell receptor on the surface of circulating cells, a well-recognized sign that the cells have encountered their target ligand and internalized their sensor, confirming that IMM60 reached and stimulated its intended audience in living patients. Alongside this, the drug triggered a measurable wave of chemokines, the signaling molecules that guide immune cells to sites of inflammation and tumors. Monocyte chemoattractant protein-1, known as MCP-1 or CCL2, peaked at twenty-four hours with a geometric mean fold-change of 4.2 times baseline, a statistically significant rise. Interferon-gamma-inducible protein 10, or IP-10, rose faster, peaking at four hours with a 2.4-fold increase, also statistically significant.

Notably, the broad family of pro-inflammatory cytokines, the molecules most associated with the dangerous systemic immune storms that can accompany overzealous immunotherapy, showed no consistent elevation over baseline. This pattern, a targeted rise in chemokines that recruit immune cells without a indiscriminate inflammatory surge, is precisely the profile a rational iNKT agonist should produce. It suggests the drug can orchestrate immune traffic toward tumors while sparing patients the collateral damage of systemic inflammation, a balance that has been the holy grail of this therapeutic class since alpha-galactosylceramide first entered human testing years ago.

On the clinical side, the trial was small and early-stage, so dramatic tumor shrinkage was never the realistic expectation, particularly in a population this heavily pretreated. Even so, the signals were encouraging. Stable disease was the best overall response in the majority of assessed patients, and when the investigators examined individual tumor lesions, they found reductions in thirty percent of the lesions evaluated. Among these was a patient with melanoma whose cancer had resisted both BRAF and MEK inhibitor targeted therapy and PD-1 checkpoint blockade, one of the hardest treatment scenarios in modern oncology. Median progression-free survival across the treated group was 2.9 months, a modest figure that nonetheless reflects the refractory nature of the disease in these patients and the fact that the trial’s dose-escalation design was built to find a safe dose, not to maximize efficacy.

The authors conclude that liposomal IMM60 is well tolerated, shows clear evidence of iNKT cell target engagement and early chemokine induction, and produced signs of disease control in heavily pretreated and PD-1-refractory patients, findings they say support further evaluation of the drug in combination with checkpoint inhibition. The trial, sponsored and funded by iOx Therapeutics and conducted at sites including the Churchill Hospital in Oxford and Hammersmith Hospital in London, was prospectively registered in January 2021. As with any phase I study, the road ahead is long: larger trials will need to determine whether the immune activation seen in blood tests translates into meaningful extension of survival, and which doses and schedules best combine IMM60 with checkpoint blockade. But for a therapeutic concept that has struggled for years to make the leap from laboratory promise to clinical reality, this first-in-human dataset offers something precious: proof that a next-generation iNKT agonist can be given safely to cancer patients, can be seen doing its molecular job, and may be stirring the immune system in tumors that have run out of options.

Subject of Research: A first-in-human phase I trial of the liposomal iNKT cell agonist IMM60 with or without pembrolizumab in advanced melanoma and non-small cell lung cancer

Article Title: IMP-MEL: a phase I first-in-human study of IMM60 with or without pembrolizumab in advanced melanoma and non-small cell lung cancer (NSCLC)

Article References: Coupe, N., Kramer, R., Pinato, D. J., Middleton, M., Gileadi, U., Thompson, D., McJannett, N., Santo, C. D., Poe, R., & Walters, I. (2026). IMP-MEL: a phase I first-in-human study of IMM60 with or without pembrolizumab in advanced melanoma and non-small cell lung cancer (NSCLC). Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08980-8

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08980-8

Keywords: IMM60, iNKT cells, cancer immunotherapy, melanoma, non-small cell lung cancer, pembrolizumab, phase I trial, liposomal formulation, alpha-galactosylceramide, CD1d, checkpoint inhibitor, chemokines

BIN1, short for Bridging Integrator 1, is an adaptor protein best known for its role in shaping cell membranes and regulating the dynamics of the cytoskeleton. In neurons, previous work has linked BIN1 to defects in intracellular transport, synaptic dysfunction and the accumulation of tau pathology, one of the hallmark protein abnormalities of Alzheimer’s disease. What has remained far less clear is what BIN1 does in microglia, the resident immune cells that account for a growing share of Alzheimer’s genetic risk. Because neuroinflammation is a defining feature of the disease, the researchers set out to determine whether microglial BIN1 influences the inflammatory tone of the brain, both in the healthy resting state and under conditions of immune challenge.

To answer that question, the team engineered mice in which the Bin1 gene could be deleted specifically in microglia, creating what researchers call a microglia-specific conditional knockout, or Bin1cKO, mouse. This approach matters because BIN1 is expressed in multiple brain cell types, and deleting it everywhere would make it impossible to attribute any observed effect to a single cell population. By restricting the deletion to microglia, the researchers could ask a precise question: does the loss of BIN1 within these immune cells alone change how the brain responds to inflammation? The experimental procedures were carried out in compliance with European and Greek legislation on laboratory animal use and approved by the Animal Care and Use Committee of the Hellenic Pasteur Institute.

The first analytical tool the team deployed was single-nucleus RNA sequencing, a technique that captures the gene expression profile of individual cell nuclei and allows researchers to identify distinct cellular states with unprecedented resolution. By profiling the brains of the Bin1cKO mice, the investigators discovered that the deletion of BIN1 did not leave microglia untouched even under normal, homeostatic conditions. Instead, the loss of the protein produced measurable alterations in microglial morphology, the intricate branching structure that these cells use to survey their environment, and shifted their inflammatory gene expression profile. In other words, removing BIN1 appeared to release the cells from a state of restraint, nudging them toward an activated phenotype before any external challenge had even occurred.

The most dramatic effects, however, emerged when the animals were subjected to systemic inflammation, an immune challenge elsewhere in the body that sends inflammatory signals cascading into the brain. Under these conditions, the Bin1cKO microglia proved sufficient to alter the expression of key genes that regulate microglial proliferation and pro-inflammatory activation. The researchers found that the response was driven largely by an enhancement of the type I interferon pathway, a signaling system normally mobilized to fight viral infections but increasingly implicated in chronic neurodegenerative disease. Alongside the interferon signature, the knockout microglia showed elevated expression of pro-inflammatory cytokines, the chemical messengers of inflammation, chemokines that recruit additional immune activity, and complement components, a branch of the immune system that has been linked to synapse loss in Alzheimer’s disease.

Type I interferon signaling has become one of the most intriguing threads in modern Alzheimer’s research. In the healthy brain, this pathway helps microglia respond rapidly to threats, but sustained or excessive activation can be damaging, promoting a chronic inflammatory environment that stresses neurons and disrupts synaptic connections. The new findings suggest that BIN1 normally acts as a molecular brake on this system, keeping the interferon response within bounds. When the protein is absent, the brake comes off, and the microglia respond to inflammatory signals with disproportionate vigor. This mechanism offers a concrete biological explanation for how a genetic risk factor identified through population genetics translates into cellular behavior inside the brain.

Perhaps the most compelling aspect of the study is its comparative analysis across species. The researchers compared the transcriptomic signature of the inflammation-induced Bin1cKO mouse microglia with gene expression data from human microglia in the early stages of Alzheimer’s disease. The comparison revealed genes showing similar trends of transcriptional change in both settings, suggesting that the inflammatory program unleashed by BIN1 deficiency in mice overlaps with the molecular changes occurring in human patients as the disease begins to take hold. This kind of cross-species convergence is a valuable benchmark, because animal models of Alzheimer’s disease have often been criticized for failing to capture the biology of the human condition. Here, the model appears to reproduce a disease-relevant inflammatory signature.

The implications of the work extend in several directions. For one, it reframes BIN1 not merely as a neuronal protein involved in tau biology and synaptic maintenance, but as a dual-function risk gene whose immune role may be equally important. If microglial BIN1 deficiency primes the brain for exaggerated inflammatory responses, then individuals carrying BIN1 risk variants could be more susceptible to inflammatory triggers throughout life, from infections to age-related immune changes. This resonates with a broader theme in Alzheimer’s research, in which cumulative inflammatory insults are thought to lower the threshold for disease onset. It also raises the possibility that therapies aimed at dampening type I interferon signaling or complement activation could be particularly beneficial in carriers of BIN1 risk alleles, an idea that would need to be tested in future studies.

Technically, the study demonstrates the power of combining cell-type-specific genetics with single-cell transcriptomics. By coupling a conditional knockout strategy to single-nucleus RNA sequencing, the researchers could dissect the contribution of a single gene in a single cell population while still capturing the full complexity of the brain’s cellular ecosystem. The phenotypic analyses of microglial morphology and the flow cytometry work, supported by the FACS Unit of the Hellenic Pasteur Institute, complemented the sequencing data by confirming that the transcriptional changes translated into visible alterations in cell structure and state. This multi-layered approach is increasingly seen as the standard for rigorous neuroimmunology, where gene expression alone can be misleading without corresponding cellular and functional validation.

There remain open questions. The study establishes that microglial BIN1 restrains inflammatory activation, but the precise molecular pathways through which the adaptor protein exerts this control, potentially involving its known roles in membrane dynamics and intracellular trafficking, have yet to be fully mapped. It is also unclear whether restoring BIN1 expression in microglia could reverse the heightened inflammatory state, or whether the effects of its loss during development are irreversible. What the research does establish, however, is a clear and testable principle: microglial BIN1 acts as a critical brake on inflammatory activation, and its deficiency shapes inflammatory susceptibility in a context directly relevant to Alzheimer’s disease. As the search for effective Alzheimer’s therapies continues, genes like BIN1 that sit at the intersection of genetic risk and immune regulation are likely to attract growing attention, both as clues to the disease’s origins and as potential targets for intervention.

Subject of Research: The role of the Alzheimer's genetic risk factor BIN1 in regulating microglial inflammatory activation and neuroinflammation

Article Title: Microglial deficiency of Alzheimer’s genetic risk factor Bin1 elicits enhanced cortical inflammatory response

Article References: Margariti, M., Thanou, I., Papadimitriou, E., Pelletier, A., Xingi, E., Antoniou, C., Kyrargyri, V., Costa, M. R., & Thomaidou, D. (2026). Microglial deficiency of Alzheimer’s genetic risk factor Bin1 elicits enhanced cortical inflammatory response. Cellular and Molecular Life Sciences. https://doi.org/10.1007/s00018-026-06434-4

Image Credits: AI Generated

DOI: 10.1007/s00018-026-06434-4

Keywords: BIN1, Alzheimer's disease, microglia, neuroinflammation, type I interferon, single-nucleus RNA sequencing, conditional knockout, cytokines, chemokines, complement, GWAS risk factor, neurodegeneration

The review’s central premise is that intestinal T-cell migration is neither random nor passive. It is orchestrated by a multilayered network of molecular signals that begins with the sphingosine-1-phosphate (S1P) system. S1P is a bioactive lipid whose concentration is high in the blood and low inside lymphoid tissues, creating a gradient that mature T cells sense through the S1PR1 receptor to exit the thymus and peripheral lymphoid organs. A surface molecule called CD69 provides a counterweight, promoting degradation of S1PR1 and transiently trapping activated T cells where they can receive further instruction. When this egress circuit malfunctions, as in alcohol-associated liver disease where circulating S1P levels rise abnormally, gut-derived T cells can flood into the periphery and amplify systemic immunopathology.

Once T cells leave lymphoid tissue, chemokine-receptor axes supply the directional map. Distinct T-cell subsets carry distinct receptor repertoires: Th1 cells express CXCR3 and CCR5 and respond to inflammatory chemokines such as CXCL9, CXCL10, and CXCL11; Th17 cells typically express CCR6 and, after gut imprinting, acquire CCR9 and the integrin α4β7; regulatory T cells use CCR9, CCR6, and α4β7 to reach the mucosa and maintain tolerance. Direction alone is not enough, however. Tissue entry requires integrins, molecular clamps that switch from a low-affinity resting state to a firm-binding conformation upon chemokine activation. The ligand MAdCAM-1, enriched in gut vasculature, partners with α4β7 to grant intestinal homing, while ICAM-1 and VCAM-1 mediate adhesion and transendothelial migration elsewhere. In inflammatory bowel disease, endothelial expression of all three ligands rises, and effector T cells accumulate in the mucosa in destructive numbers.

Beneath these classical signals lies a deeper layer of regulation. The cytoskeleton converts chemical cues into physical movement: actin polymerization drives leading-edge protrusion, and coordinated microtubule remodeling maintains cellular polarity. In intestinal γδ T cells, loss of the motor protein Myo1f reduces surface expression of CCR9 and α4β7 and disrupts receptor polarization, crippling adhesion and homing. Metabolism shapes migratory capacity indirectly but powerfully. Activated Th1 and Th17 cells ramp up glycolysis to fuel rapid proliferation and tissue infiltration, while regulatory T cells favor fatty acid oxidation, though even Tregs need glycolysis to migrate actively. Hypoxia stabilizes HIF-1α, which biases differentiation toward inflammatory Th17 cells at the expense of Tregs, expanding the pool of migratory effector cells. Epigenetic mechanisms then lock these programs in place, stabilizing chromatin accessibility at migration genes such as S1pr1, Klf2, Ccr7, and Cd69; pathogenic Th17-like cells in IBD carry a distinctly open, pro-inflammatory chromatin state.

Perhaps the most striking insight of the review concerns the gut microbiota, which acts as an upstream programmer of the entire migratory apparatus. Short-chain fatty acids such as butyrate promote colonic regulatory T-cell stability by enhancing histone acetylation at the Foxp3 locus, while retinoic acid produced by gut dendritic cells induces CCR9 and α4β7 expression, with the transcription factor BATF activating the Ccr9 and Itga4 gene loci. Under pathological conditions, the same microbial signals can turn malevolent: segmented filamentous bacteria induce epithelial serum amyloid A proteins that drive inflammatory Th17 differentiation, and in glaucoma models, commensal-primed β7-positive CD4 T cells acquire gut-imprinted features and contribute to retinal ganglion cell damage. The gut, in other words, licenses T cells for journeys to organs it will never see.

These journeys define what the authors call the gut-organ axes. The lung occupies a special position because it receives the entire cardiac output, acting as a vascular filter and secondary imprinting site where pulmonary dendritic cells can confer CCR4-dependent lung-homing capacity on passing T cells. In the immune-privileged central nervous system and retina, barrier remodeling can transform once-protected tissues into selective gates: in experimental autoimmune encephalomyelitis, Th17 cells first undergo α4β7-MAdCAM-1-dependent gut homing before entering the CNS, and blocking that gut step attenuates brain inflammation. Experimental colitis can upregulate MAdCAM-1 in retinal microvessels, recruiting gut-homing CD4 T cells that injure retinal neurons. Along the metabolic axis, pancreatic β cells in type 1 diabetes express CXCL10 that recruits CXCR3-positive T cells to the islets, while in non-alcoholic steatohepatitis, α4β7-mediated recruitment of CD4 T cells to liver and gut drives fibrosis, though β7 deficiency paradoxically worsens disease in other models, a vivid illustration of context dependence.

Even bone is not exempt. Estrogen deficiency expands intestinal Th17 and TNF-producing CD4 T cells, enhances their S1PR1-dependent egress, and delivers them to the bone marrow through CXCR3, where they induce CCL20 and recruit more Th17 cells, fueling osteoclast activation and bone loss. Conversely, the bone-anabolic effect of intermittent parathyroid hormone depends on microbiota-derived butyrate, which enhances Treg responses and promotes bone formation through CD8 T-cell-derived Wnt10b. The same axis that destroys bone in one hormonal context builds it in another, underscoring the review’s argument that pathological migration is a mismatch between migratory direction, cell subset, and tissue context rather than simply too much trafficking.

The therapeutic implications are already substantial. S1PR modulators such as fingolimod, ozanimod, siponimod, and etrasimod functionally antagonize S1PR1, sequestering lymphocytes in lymphoid tissues, and have transformed treatment of relapsing multiple sclerosis and ulcerative colitis, though first-generation agents’ cardiovascular side effects pushed development toward greater receptor selectivity. Integrin antagonists represent the most clinically mature class: natalizumab blocks α4 broadly but carries a risk of progressive multifocal leukoencephalopathy by impairing CNS immune surveillance, prompting the development of the gut-selective anti-α4β7 antibody vedolizumab, proven for both ulcerative colitis and Crohn’s disease. Yet even vedolizumab’s efficacy varies across populations, and a phase III trial in Chinese patients with Crohn’s disease missed its primary endpoint, likely reflecting differences in prior biologic exposure, microbiota composition, and compensatory trafficking pathways. Chemokine blockade has proven harder: the CCR5 antagonist maraviroc shows promise in graft-versus-host disease prophylaxis, but elevated CXCL9 and CXCL10 in non-responders reveal how readily the CXCR3 axis compensates, and the anti-CCR4 antibody mogamulizumab can deplete protective central memory CD8 T cells alongside its intended targets.

The review also highlights indirect and adjunctive strategies. Commonly used drugs reshape the migratory microenvironment: proton pump inhibitors can disrupt tight junctions and alter microbiota, NSAIDs activate TLR4-NF-κB signaling that creates chemotactic conditions for effector T cells, and statins may interfere with RhoA-dependent cytoskeletal remodeling. Microbiota-based interventions, including probiotics, propionate supplementation in multiple sclerosis, and fecal microbiota transplantation, show real but heterogeneous promise, with FMT success depending heavily on donor-recipient ecological matching and carrying risks of transmitting drug-resistant organisms. Even lifestyle factors matter: chronic stress elevates glucocorticoids that suppress CCR9-mediated chemotaxis and α4β7-dependent adhesion, acute exercise mobilizes cytotoxic lymphocytes into circulation, and lymphocyte trafficking follows circadian rhythms, suggesting that the timing of migration-targeted therapy could one day be optimized.

The authors conclude that the future lies not in broadly suppressing T-cell movement but in selectively restraining pathological migration while preserving barrier defense, immune surveillance, and antitumor immunity. Precision tools are emerging to support this shift: fluorescently labeled vedolizumab can visualize α4β7-positive target cells in inflamed mucosa, single-cell multi-omics and spatial transcriptomics can resolve which T-cell subsets truly drive disease, and candidate biomarkers such as soluble MAdCAM-1, circulating α4β7-positive T cells, and genetic variants in S1PR1, ITGA4, ITGB7, and CCR6 may guide patient stratification. Combination regimens such as the EXPLORER triple therapy of vedolizumab, adalimumab, and methotrexate in early Crohn’s disease offer cautious encouragement, though mechanistic complementarity does not always translate into clinical benefit, as disappointing trials of mogamulizumab plus nivolumab demonstrate. What emerges from this synthesis is a reframing of immune-mediated disease itself: not as a failure confined to a single tissue, but as a disorder of connectivity, in which the gut continuously imprints migrating T cells and distant organs decide, through their own chemotactic and adhesive gates, whether those cells heal or harm.

Subject of Research: Mechanisms of intestinal T-cell migration and its role in gut-organ axis diseases and migration-targeted therapies

Article Title: Intestinal T-cell migration: unraveling mechanisms and therapeutic implications

Article References: Sun, Y., Liu, Y., Xie, L., Zhu, L., & Peng, W. (2026). Intestinal T-cell migration: unraveling mechanisms and therapeutic implications. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.10.019

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.10.019

Keywords: T-cell migration, intestinal immunity, S1P-S1PR signaling, chemokines, integrins, gut-organ axis, inflammatory bowel disease, colorectal cancer, microbiota, vedolizumab, immune regulation, precision medicine

The study, conducted by Suzanne Abbring, Bart Moerings, and colleagues at Wageningen University and partner institutions, used a well-established “two-hit” mouse model to reproduce the clinical sequence seen in intensive care units. The first hit was cecal ligation and puncture, or CLP, a surgical procedure in which the cecum is ligated and pierced with a needle, allowing gut bacteria to leak into the abdominal cavity and trigger polymicrobial sepsis. The second hit, delivered four days later, was an intranasal dose of Pseudomonas aeruginosa, a notorious hospital-acquired pathogen that causes pneumonia. The four-day interval was deliberately chosen because prior work shows the initial hyperinflammatory phase of sepsis resolves within two to three days, after which mice enter the immunosuppressive phase, mirroring the timing of nosocomial infections in humans, which typically emerge three to five days after hospitalization.

Importantly, the researchers designed their first hit to be relatively mild rather than lethal. The procedure produced less than six percent mortality over four days, with a maximum average Clinical Severity Score of just 2.5 out of 10, yet it was clearly sufficient to induce systemic inflammation. Four hours after surgery, CLP mice showed significantly elevated circulating levels of the pro-inflammatory cytokines TNF-alpha, IL-6, and MCP-1 compared with sham-operated controls, and they lost roughly fifteen percent of their body weight over the following days. This sublethal design was intentional: the goal was not to study death from sepsis itself, but to create a clinically relevant state of immune weakening and then examine, in fine detail, how the body responds when a second pathogen arrives.

To find the right dose for the second hit, the team tested a range of Pseudomonas inocula, from one million to one hundred million colony-forming units, and the results revealed a strikingly narrow therapeutic window. At the lowest dose, one million CFU, neither sham nor CLP mice showed any signs of infection at all. At one hundred million CFU, all animals, regardless of prior surgery, rapidly reached humane endpoints, meaning they succumbed to the overwhelming bacterial challenge itself rather than to any immunosuppression. Only at the intermediate dose of fifty million CFU did the difference between the groups emerge: CLP mice maintained persistently elevated clinical severity scores twenty hours after infection, while sham mice began to recover. This dose-dependence, the authors note, means the optimal inoculum cannot simply be extrapolated from previous studies, since differences in mouse strain, sex, bacterial strain, and route of administration can dramatically shift outcomes.

When the researchers examined the lungs twenty hours after infection, they uncovered the molecular signature of immunosuppression. Although the number of Pseudomonas colonies did not differ significantly between sham and CLP animals, the pulmonary cytokine response told a very different story. CLP mice mounted significantly weaker production of TNF-alpha and IL-6, the canonical pro-inflammatory signals that recruit and activate immune defenses, compared with sham mice given the same bacterial dose. Levels of interferon-gamma were also reduced in CLP animals, and this suppression was present even in animals instilled with saline rather than bacteria, indicating it reflected the lingering effects of the first hit rather than the second. Surprisingly, levels of IL-10, an immunosuppressive cytokine often elevated after sepsis in previous studies, were actually lower in the lungs of CLP animals, a discrepancy the authors attribute to differences in experimental design and the inclusion of proper saline controls.

The chemokine data reinforced the picture of a muted immune alarm. Chemokines such as CXCL9, CXCL10, and CCL22, which orchestrate the recruitment of macrophages and other leukocytes to sites of infection, failed to rise in CLP animals after Pseudomonas challenge, whereas sham mice showed clear increases. CXCL9 and CCL22 were significantly reduced across all bacterial doses tested, and CXCL10 and CXCL5 were reduced in most groups. Only CXCL1, a neutrophil-attracting chemokine, remained comparable between the two groups. Together, these findings suggest that after an initial septic insult, the lung’s ability to broadcast the molecular distress signals needed to summon cellular reinforcements is profoundly impaired, even when bacteria are physically present in the tissue.

To isolate the role of macrophages specifically, the researchers turned to an ex vivo approach. They collected spleen-derived macrophages and adherent bone marrow cells from CLP and sham animals that had not been exposed to Pseudomonas, then stimulated these cells in culture with lipopolysaccharide, the bacterial endotoxin that robustly activates macrophages. The results were unambiguous: macrophages from CLP animals released significantly lower amounts of TNF-alpha and IL-6 in response to LPS than those from sham animals, while simultaneously producing significantly higher levels of the anti-inflammatory cytokine IL-10. This shift, in which pro-inflammatory output is blunted while IL-10 production is preserved or enhanced, is a hallmark of endotoxin tolerance and immune paralysis. Critically, the fact that CLP macrophages could still produce IL-10 demonstrated that the cells were not dead or completely inert; they retained functional capacity but had been reprogrammed toward a suppressed state.

That residual capacity opened the door to the study’s most intriguing experiment. Building on their earlier work showing that arabinoxylans, non-digestible polysaccharides found in cereal grains, can induce trained immunity in human macrophages, the team exposed spleen-derived macrophages from CLP and sham animals to five different arabinoxylan preparations before LPS stimulation. The results were preliminary but promising. A rice bran-derived preparation significantly enhanced TNF-alpha production in macrophages from CLP animals, partially reversing the immunosuppressed phenotype, while other rice-derived preparations showed moderate effects on TNF-alpha or IL-6 production. Rice hull and two other rice bran fractions showed tendencies toward restored cytokine output, though not all preparations were effective, and wheat bran had no impact. The authors stress that this pilot experiment lacked the statistical power to draw firm conclusions, but it suggests that dietary fibers may hold genuine potential as immune-supportive interventions for immunocompromised patients.

The study also carries important methodological lessons for the field. The researchers found that total bacterial load in the lungs of CLP animals was elevated even in saline-instilled controls, likely reflecting bacterial dissemination from the abdominal infection rather than impaired pulmonary clearance of Pseudomonas. This finding underscores the necessity of including saline-instilled CLP control groups when assessing susceptibility to secondary infection, a control that several previous studies omitted. The authors also acknowledge limitations: their macrophage cultures were derived from heterogeneous cell populations, the analysis of macrophage polarization states such as M1 and M2 phenotypes was not performed, and sample sizes were based on prior experience rather than formal power calculations. Only male mice were studied, so whether the findings extend to females remains unknown.

Nevertheless, the broader significance of the work is clear. By systematically mapping the cytokine, chemokine, and cellular responses across multiple bacterial doses, the study provides one of the most comprehensive characterizations to date of the immunosuppressive phase that follows sepsis-like insults. It confirms that macrophage dysfunction, rather than simply an inability to clear bacteria, lies at the heart of vulnerability to secondary pneumonia, and it demonstrates that these silenced cells can be coaxed back toward responsiveness with the right stimuli. The ex vivo LPS challenge model, the authors argue, offers a practical and ethically advantageous platform for screening immune-enhancing compounds before moving into animal or human studies, potentially reducing animal use while accelerating the search for therapies. As antibiotic resistance rises and populations age, strategies that restore immune resilience, whether through dietary fibers, targeted immunomodulators, or combinations thereof, may become essential tools for protecting the millions of patients each year whose weakened defenses leave them exposed to the opportunists waiting in the hospital ward.

Subject of Research: Macrophage immunosuppression and secondary Pseudomonas aeruginosa pneumonia susceptibility in a murine two-hit sepsis model

Article Title: Macrophage immunosuppression in a two-hit murine Pseudomonas aeruginosa -induced pneumonia model

Article References: Abbring, S., Moerings, B. G., Furber, M., Witkamp, R. F., Govers, C., van Bergenhenegouwen, J., Mes, J. J., & van Norren, K. (2026). Macrophage immunosuppression in a two-hit murine Pseudomonas aeruginosa-induced pneumonia model. Heliyon, 12(15), Article e45561. https://doi.org/10.1016/j.heliyon.2026.e45561

Image Credits: AI Generated

DOI: 10.1016/j.heliyon.2026.e45561

Keywords: macrophages, immunosuppression, sepsis, Pseudomonas aeruginosa, pneumonia, two-hit model, cecal ligation and puncture, cytokines, chemokines, arabinoxylans, endotoxin tolerance, innate immunity

The research team used a technology called targeted proteomics, specifically the Olink proximity extension assay platform, to measure the expression of hundreds of proteins simultaneously in tiny volumes of blood. This matters enormously in neonatal care, where every milliliter of a premature infant’s blood is precious and repeated sampling is risky. The study drew on blood samples collected between December 2019 and July 2023 at two level IV neonatal intensive care units, one in Rotterdam in the Netherlands and one in Poznań in Poland. The clinical cohort comprised fifteen preterm infants who developed late-onset sepsis, all born before 30 weeks of gestation, alongside eight clinically stable control infants of similar gestational age who showed no signs of systemic inflammation.

Blood was drawn from the septic infants at three critical moments: at the onset of the septic episode, 24 hours later, and 48 hours after diagnosis. The first sample had to be taken within six hours of the start of antibiotic treatment, ensuring the researchers captured the inflammatory landscape as close to the biological beginning of the episode as possible. After rigorous quality control removed proteins that failed technical standards or fell below the limit of detection in more than half of the septic samples, 355 proteins remained for analysis. To validate the reliability of the measurements, the team cross-checked their proteomic readings against conventional laboratory values, finding a strong correlation between the platform’s IL-6 protein readings and independently measured plasma IL-6 concentrations, as well as a robust correlation between IL-6 and TNF protein signals.

The headline finding was striking: 66 proteins showed statistically significant and biologically meaningful differences between septic and non-septic infants at the moment of diagnosis. The researchers applied a dual threshold, requiring both an adjusted p-value below 0.05 and an absolute log2 fold change greater than 0.5, to ensure that only changes large enough to matter clinically were counted. Forty-one of these proteins were upregulated in sepsis, and they were overwhelmingly molecules of immune communication: interleukins such as IL-1β, IL-6, IL-10, IL-15, IL-17A, and IL-18, chemokines including CCL-3, CCL-4, CCL-7, CCL-20, and CCL-23, and a battery of receptor-associated proteins that help immune cells recognize and respond to pathogens. IL-6 itself showed the single largest increase, which the authors note was partly expected because elevated IL-6 was one of the enrollment criteria for the original trial from which the samples came.

Perhaps more intriguing than the proteins that rose were the ones that fell. Twenty-five proteins were expressed at significantly lower levels in septic infants compared with controls, and these were not primarily inflammatory molecules. Instead, they were proteins involved in development, growth, and metabolism, including WNT9A, NTF3, PSPN, VEGFD, and NPPC, along with adhesion molecules such as ICAM4 and LAMA4 and metabolic proteins like ALDH3A1 and OPN3. This downregulation of growth and developmental pathways during infection offers a molecular echo of what neonatologists have long observed at the bedside: infants who survive neonatal infections face higher risks of impaired neurodevelopment and poor growth. The finding suggests that sepsis does not merely unleash inflammation in these tiny patients; it actively suppresses the biological programs that build their bodies and brains.

The longitudinal design of the study added another layer of insight. By tracking protein levels across the first 48 hours of the septic episode, the researchers discovered that the proteomic storm is remarkably short-lived once treatment begins. Fifty-nine proteins changed significantly between the onset sample and the 24-hour sample, while 40 showed significant changes between onset and 48 hours. By contrast, only three proteins, FLT3LG, SCGB3A2, and SH2D1A, continued to change significantly between the 24-hour and 48-hour marks. In other words, most of the molecular upheaval had already settled within two days of diagnosis and the start of antibiotics. Thirteen proteins, including IL-1β, CXCL8, and several chemokines, required more than 24 hours before their expression shifted significantly, hinting at a slower second wave of the immune response.

To determine which of these protein changes were direct consequences of bacteria meeting blood, rather than downstream effects of the full-body inflammatory response, the team performed a clever parallel experiment. They took fresh whole blood from ten preterm infants who had never developed sepsis and exposed it in the laboratory to live E. coli, a Gram-negative bacterium, and Staphylococcus epidermidis, a Gram-positive species that is a common cause of late-onset sepsis in intensive care units. The blood was diluted five-fold, incubated with the bacteria for six hours at body temperature, and then analyzed with a targeted inflammation panel. This in vitro model isolates the immediate interaction between pathogens and circulating immune cells, free from the influence of the vascular endothelium, the liver, and the other organ systems that shape the systemic response in a living patient.

The results of this comparison were illuminating. Of the 22 proteins that overlapped between the clinical and in vitro analyses, 18 could be induced by bacterial exposure, and these were exclusively cytokines and chemokines, including IL-6, IL-10, TNF, IFN-γ, CXCL8, and several CCL chemokines, along with oncostatin M. Four proteins, IL-2, IL-17A, IL-24, and NTF3, fell below the detection limit in most stimulated samples, suggesting they cannot be directly induced by bacterial contact and likely reflect secondary systemic processes in actual sepsis. A handful of proteins showed reversed patterns between the two settings, being upregulated in patients but downregulated in the dish, or vice versa, underscoring how much the intact body contributes to the septic protein signature beyond the blood itself. Notably, E. coli and S. epidermidis produced largely similar responses, with no distinct protein signature separating Gram-negative from Gram-positive stimulation, a finding consistent with earlier work on cytokine production in preterm cord blood.

The authors are candid about the limitations of their exploratory design. The cohort of fifteen cases and eight controls was small and not calculated a priori, which limits statistical power and likely explains why subgroup analyses comparing culture-positive with culture-negative episodes, or Gram-positive with Gram-negative infections, yielded no consistent differences. The patients were selected precisely because they had markedly elevated IL-6 or CRP, introducing selection bias, and all received pentoxifylline as part of a dose-optimization trial, which may have influenced protein expression over time. The control infants were also more mature and heavier than the septic group, and no non-infectious inflammatory control group was included, leaving open the question of how specific these protein signatures are to infection rather than inflammation in general.

Even so, the study demonstrates the feasibility and promise of combining longitudinal clinical sampling with controlled in vitro stimulation to separate direct pathogen-induced immune activation from secondary systemic responses. The proteins that rose and fell in parallel across both settings, particularly the core inflammatory mediators, emerge as the strongest candidates for future diagnostic development, while the downregulated growth and metabolic proteins may illuminate why neonatal infection leaves lasting developmental scars. Before any of these molecules reach the clinic, they must be validated in larger, independent, and unselected cohorts, ideally with targeted panels focused on the most promising candidates to reduce false discoveries. If that validation succeeds, clinicians could one day have a rapid, blood-sparing molecular test that catches sepsis hours earlier than CRP or procalcitonin can, sparing fragile preterm infants both the delay in treatment and the unnecessary antibiotics that carry their own dangers.

Subject of Research: Targeted proteomic biomarkers of late-onset neonatal sepsis in preterm infants

Article Title: Targeted proteomics in late-onset neonatal sepsis: an exploratory analysis

Article References: Schouten, J. S., Kurul, Ş., Gorissen, R., Reiss, I. K. M., Willemsen, S. P., Mazela, J., Unger, W. W. J., Simons, S. H. P., Jans, J., & Taal, H. R. (2026). Targeted proteomics in late-onset neonatal sepsis: an exploratory analysis. Pediatric Research. https://doi.org/10.1038/s41390-026-05554-8

Image Credits: AI Generated

DOI: 10.1038/s41390-026-05554-8

Keywords: neonatal sepsis, preterm infants, proteomics, biomarkers, Olink, cytokines, chemokines, inflammation, NICU, E. coli, S. epidermidis, Pediatric Research

The story begins with the pulp–dentin complex itself, the integrated functional unit that keeps a living tooth alive. Odontoblasts line the periphery of the pulp space and extend processes into the dentinal tubules, serving as sentinels that detect external threats and deposit tertiary dentin as a defensive barrier. Fibroblasts, the most abundant stromal cells in the pulp, produce and maintain the extracellular matrix, while dental pulp stromal cells, or DPSCs, carry remarkable regenerative and immunomodulatory properties, including the ability to differentiate into odontoblast-like cells and contribute to reparative dentin formation. When caries breaches the enamel and advances through dentin, a dynamic network of interdependent relationships emerges among odontoblasts, stromal cells and immune cells, and it is within this network that the Korean team went hunting for the rules of communication.

Macrophages were the obvious suspects. These innate immune cells are the pulp’s frontline defenders, recognizing pathogen-associated molecular patterns through Toll-like receptors and mounting inflammatory responses against bacterial invasion. But macrophages are also indispensable mediators of tissue remodeling, secreting trophic factors such as TGF-beta, VEGF and IGF-1 that regulate the proliferation, migration and differentiation of resident progenitor cells. To see how macrophages behave during actual disease, the researchers examined human dental pulp tissue from healthy teeth and teeth with moderate or severe caries, using immunofluorescence to track CD68-positive macrophages. In healthy pulp, macrophages were sparsely distributed throughout the tissue. As caries progressed, their numbers surged, and they clustered beneath regions of advanced decay near the odontoblast layer.

The most striking observation was physical contact. The proportion of macrophages in intimate contact with Thy-1-positive DPSCs rose from 11.2 percent in healthy teeth to 23.7 percent in moderate caries and 48.7 percent in severe caries, suggesting that these immune–stromal encounters are not incidental but part of an organized defensive response. In vitro, the team co-cultured differentiated human macrophages with primary DPSCs and watched the two cell types lock together, extending lamellipodia and filopodia-like protrusions visible under scanning electron microscopy. Macrophages in direct contact with DPSCs showed markedly increased filamentous actin intensity, particularly at the cell–cell interface, a hallmark of intercellular adhesion mechanisms at work.

What molecule was doing the gluing? The researchers profiled adhesion components by RNA sequencing and tested two hypotheses: direct homophilic binding between matching cell-adhesion molecules, or indirect communication through an extracellular matrix intermediary. The homophilic route failed, as macrophages and DPSCs showed no matching cadherin or ICAM-family expression patterns. The matrix route, however, lit up. DPSCs predominantly expressed fibronectin and type I collagen, while macrophages abundantly expressed the integrin subunits ITGA5 and ITGB1, the canonical receptors for fibronectin. Computational ligand–receptor prediction with CellPhoneDB confirmed statistically significant interactions between fibronectin on DPSCs and multiple integrin receptors on macrophages. Structured illumination microscopy then revealed that integrin alpha-5 clusters on macrophages aligned precisely with fibronectin deposited on the DPSC surface, forming the activated, clustered configuration characteristic of functional adhesion.

The functional proof was decisive. A synthetic RGD peptide that blocks integrin–ligand binding reduced macrophage–DPSC contact in a concentration-dependent manner, while collagenase treatment had no effect. CRISPR-Cas9 knockout of ITGA5 in macrophages slashed both the proportion and the duration of contacts with DPSCs, as live imaging over 48 hours demonstrated. Downstream, phosphorylated focal adhesion kinase rose in macrophages cultured on fibronectin-coated surfaces and climbed even higher in co-culture, implicating the fibronectin–integrin–FAK axis as the signaling conduit between the two cell types.

Then came the transformation. Bulk RNA sequencing of sorted macrophages revealed that co-culture with DPSCs shifted their chemokine repertoire dramatically: pro-inflammatory CCL2 and CCL3 were downregulated, while a suite of ELR-positive CXC chemokines—CXCL2, CXCL3, CXCL5, CXCL6 and CXCL8—known for their angiogenic activity were upregulated, alongside VEGFA. Macrophages seeded on fibronectin-coated plates upregulated these pro-angiogenic factors in a dose-dependent fashion, and silencing FN1 in DPSCs suppressed the effect, confirming fibronectin as the trigger. Flow cytometry showed the macrophages shifting toward an M2-like phenotype, with CD206 rising while CD86 stayed flat. The mechanism ran through NF-kappa-B: p65 accumulated in both cytoplasm and nucleus of co-cultured macrophages, and a live-cell GFP reporter showed that fibronectin-coated surfaces drove NF-kappa-B activity roughly 90 percent higher than LPS treatment, while collagen 1 surfaces did nothing.

The consequences for blood vessels were immediate. Conditioned medium from macrophage–DPSC co-cultures dramatically enhanced tube formation by human umbilical vein endothelial cells, increasing the number of junctions, segments and meshes compared with medium from either cell type alone. Endothelial cells exposed to co-culture medium also showed fewer apoptotic membrane blebs and reduced cleaved caspase-3, indicating improved survival. Blocking CXCR2 or VEGFR signaling with specific inhibitors attenuated both angiogenesis and endothelial survival, pinning the effect on the newly identified chemokine and VEGF pathways. An integrated single-cell RNA sequencing atlas of nearly 20,000 human pulp cells, analyzed with the CellChat framework, independently confirmed the story in real tissue: as caries progressed from healthy to severe, total cell–cell interactions exploded from 278 to 2,470, macrophage–endothelial CXCL signaling strengthened markedly, and macrophages emerged as central hubs of the angiogenic communication network.

The final test was translational. In a canine model of pulp revascularization using immature premolar teeth, the researchers applied fibronectin as a final canal irrigation and on a collagen sponge scaffold, following American Association of Endodontists guidelines in a split-mouth design with 22 roots per group. Eight weeks later, micro-computed tomography showed that fibronectin-treated roots had significantly greater cross-sectional dentin area (3.40 versus 2.39 square millimeters) and far more frequent apical closure (59.1 percent versus 22.7 percent). Histology revealed organized layers of polarized odontoblast-like cells, dentinal tubule-like structures and dentin sialoprotein-positive staining in the treated roots, along with abundant new blood vessels and CD14-positive, CD163-positive M2 macrophages in the stromal region—precisely the cellular signature the in vitro work had predicted. Fibronectin itself was localized along the regenerated odontoblast layer, mirroring its arrangement in healthy human pulp.

The implications reach well beyond the dental chair. Because fibronectin is an endogenous protein with established biocompatibility, it carries minimal risk of adverse reactions compared with exogenous growth factors or synthetic biomaterials, and its angiogenic capabilities suggest potential applications in soft-tissue regeneration, bone-tissue engineering and scaffold-based therapies across regenerative medicine. For the millions of children and adults with immature necrotic teeth—a population for whom conventional root canals arrest root development and increase fracture risk—the prospect of a simple, biologically grounded irrigation solution that coaxes the body’s own immune and stromal cells into rebuilding a living pulp is genuinely tantalizing. The authors caution that species differences in pulp biology, optimization of delivery parameters and long-term follow-up studies all stand between this canine model and human clinical practice. But the core discovery stands: a humble matrix protein, long viewed as passive scaffolding, is in fact an active conductor of the immune–stromal orchestra that turns a damaged, infected pulp environment into a regenerative niche. Teeth, it turns out, may know how to heal themselves—we just needed to learn the language they use to ask for help.

Subject of Research: Fibronectin-mediated macrophage–stromal cell crosstalk driving angiogenesis and regeneration of the dental pulp–dentin complex

Article Title: Fibronectin-guided immune–stromal cell crosstalk promotes angiogenesis in pulp–dentin complex regeneration

Article References: Jeong, S., Park, S. Y., Ku, H., Eom, B. S., Kim, D., & Kim, J. M. (2026). Fibronectin-guided immune–stromal cell crosstalk promotes angiogenesis in pulp–dentin complex regeneration. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01863-4

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01863-4

Keywords: fibronectin, macrophages, dental pulp stem cells, angiogenesis, dental caries, pulp revascularization, extracellular matrix, integrins, regenerative dentistry, NF-kappa-B, chemokines, tissue regeneration

The research team, led by Angelina Zimenko and Jia Zhu with colleagues at the University of Washington and the Fred Hutchinson Cancer Center, set out to examine a question that has been surprisingly underexplored. Interferon gamma is well established as a critical weapon in the antiviral arsenal of tissue-resident T cells, the immune sentinels that patrol mucosal surfaces and respond when HSV-2 attempts to reactivate from its latent state in sensory neurons. What has remained murky is how the target cells of that signal, the epithelial cells of the genital skin and mucosa, respond to it, and whether differences in that response could help explain why some people develop lesions while others do not.

To address this, the investigators worked with primary keratinocytes, the dominant epithelial cell type of the outer genital tissue, obtained from donors with well-characterized HSV-2 infection. Crucially, the donors fell into two clinically distinct groups: those with asymptomatic infection, who shed virus without developing lesions, and those with ulcerative disease, who experience recurrent genital sores. The researchers also isolated donor-matched fibroblasts, the structural cells of the underlying dermis, allowing them to compare epithelial and stromal responses within the same individual. This paired design gave the team a way to isolate cell-type-specific behavior from person-to-person variation.

The first major finding concerned sheer sensitivity. Keratinocytes turned out to be remarkably responsive to interferon gamma, altering their gene expression at concentrations far lower than those typically used in laboratory studies of the cytokine. This matters because the doses commonly employed in cell culture experiments have often been orders of magnitude higher than what immune cells are thought to deliver locally in tissue. By probing responses across a range of physiologically relevant interferon gamma concentrations, the researchers revealed that epithelial cells are tuned to detect and react to very faint cytokine signals, a property that previous work had substantially underestimated.

The comparison with fibroblasts sharpened the picture. Across donors, keratinocytes showed greater sensitivity to interferon gamma stimulation than their matched fibroblasts, and the epithelial response was dominated by robust induction of chemokines, the secreted proteins that act as homing beacons for circulating immune cells. Among these, CXCL10 stood out. It was the most sensitive and most strongly induced gene in the dataset, ramping up rapidly even at the lowest interferon gamma doses tested. CXCL10 is a well-known ligand for the chemokine receptor CXCR3, which is expressed on activated T cells and other immune populations, making it a plausible molecular bridge between cytokine signaling and the recruitment of antiviral lymphocytes to sites of viral reactivation.

The most clinically significant result emerged when the researchers compared keratinocytes from the two donor groups. Epithelial cells from individuals with asymptomatic HSV-2 infection mounted significantly stronger responses to interferon gamma than cells from donors with ulcerative disease, and the difference was most pronounced at the low, physiologically relevant cytokine concentrations. The heightened responsiveness was evident both at the messenger RNA level and at the protein level, indicating that the cells from asymptomatic donors were not merely transcribing chemokine genes more vigorously but actually secreting more of the corresponding proteins. In effect, the epithelial barrier of people who never develop lesions appeared intrinsically better wired to broadcast an immune-recruitment alarm when interferon gamma arrives.

Delving into the signaling machinery, the team found that the enhanced response correlated with increased nuclear localization of phosphorylated STAT1, the transcription factor that carries the interferon gamma signal from the cell surface receptor into the nucleus. Interestingly, this difference was not explained by higher baseline expression of the interferon gamma receptor or of STAT1 itself, which were similar across donor groups. Instead, the asymptomatic donors’ keratinocytes appeared to process the incoming signal more efficiently, amplifying the downstream transcriptional output. This suggests that the variation lies in the dynamics of the JAK-STAT signaling pathway rather than in the simple abundance of its components, a distinction that could guide future mechanistic studies of interferon responsiveness in epithelial barriers.

An important nuance concerns the direct antiviral effect of the cytokine. When the researchers pretreated keratinocytes with interferon gamma before exposing them to HSV, the cytokine suppressed viral replication to a similar degree in cells from both donor cohorts. In other words, the intrinsic antiviral state that interferon gamma induces in epithelial cells was not obviously stronger in the asymptomatic group. What differed was the chemokine output. The authors propose, therefore, that the advantage enjoyed by asymptomatic individuals may lie less in the epithelium’s ability to block the virus directly and more in its capacity to summon antiviral immune cells to the tissue through vigorous chemokine production, particularly CXCL10, thereby containing reactivation events before they escalate into visible lesions.

Taken together, the findings reframe the epithelium as an active participant in the immunology of genital herpes rather than a passive substrate for viral replication. Tissue-resident T cells clearly supply the interferon gamma signal, but the study indicates that the clinical outcome of that signal depends on how loudly the epithelial target cells answer. Intrinsic variation in epithelial interferon gamma responsiveness emerges as a candidate host factor associated with whether HSV-2 infection runs a symptomatic or silent course, and CXCL10-mediated immune recruitment is highlighted as a key mechanism potentially linking T cell cytokine signaling to epithelial antiviral defense. The researchers caution that their work identifies an association and a plausible mechanism, and that establishing causation in human infection will require further study.

The implications extend beyond basic virology. Therapeutic vaccines for genital herpes, which aim to boost T cell responses in the genital tract, implicitly rely on the responsiveness of target tissues to the cytokines those T cells produce. If a substantial fraction of the population has epithelial cells that respond weakly to interferon gamma, strategies that amplify chemokine signaling or sensitize the JAK-STAT pathway in epithelial cells could complement vaccine approaches. Conversely, measuring epithelial interferon gamma responsiveness might eventually help stratify patients by their likelihood of symptomatic disease. As the authors note, understanding variability in the immune defenses of the epithelial barrier may prove crucial for improving both therapies and vaccine strategies against one of the world’s most prevalent chronic infections.

Subject of Research: Epithelial interferon gamma signaling and chemokine responses in herpes simplex virus type 2 infection outcomes

Article Title: Epithelial interferon-γ responsiveness shapes chemokine induction and clinical outcomes in herpes simplex virus infection

Article References: Zimenko, A., Hayman, I., Fong, Y., Monroe, L. D., Mills, M. G., Greninger, A., Johnston, C., Corey, L., & Zhu, J. (2026). Epithelial interferon-γ responsiveness shapes chemokine induction and clinical outcomes in herpes simplex virus infection. PLOS Pathogens, 22(9), e1014612. https://doi.org/10.1371/journal.ppat.1014612

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014612

Keywords: HSV-2, genital herpes, interferon gamma, keratinocytes, CXCL10, chemokines, STAT1, tissue-resident T cells, epithelial immunity, viral reactivation, PLOS Pathogens, antiviral defense