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Results for “Interleukin-10”

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PubMed2019

Dietary iron variably modulates assembly of the intestinal microbiota in colitis-resistant and colitis-susceptible mice.

Iron deficiency, a common comorbidity of gastrointestinal inflammatory disorders such as inflammatory bowel diseases (IBD), is often treated with oral iron supplementation. However, the safety of oral iron supplementation remains controversial because of its association with exacerbated disease activity in a subset of IBD patients. Because iron modulates bacterial growth and function, one possible mechanism by which iron may exacerbate inflammation in susceptible hosts is by modulating the intestinal microbiota. We, therefore, investigated the impact of dietary iron on the intestinal microbiota, utilizing the conventionalization of germ-free mice as a model of a microbial community in compositional flux to recapitulate the instability of the IBD-associated intestinal microbiota. Our findings demonstrate that altering intestinal iron availability during community assembly modulated the microbiota in non-inflamed wild type (WT) and colitis-susceptible interleukin-10-deficient (Il10-/-) mice. Depletion of luminal iron availability promoted luminal compositional changes associated with dysbiotic states irrespective of host genotype, including an expansion of Enterobacteriaceae such as Escherichia coli. Mechanistic in vitro growth competitions confirmed that high-affinity iron acquisition systems in E. coli enhance its abundance over other bacteria in iron-restricted conditions, thereby enabling pathobiont iron scavenging during dietary iron restriction. In contrast, distinct luminal community assembly was observed with dietary iron supplementation in WT versus Il10-/- mice, suggesting that the effects of increased iron on the microbiota differ with host inflammation status. Taken together, shifts in dietary iron intake during community assembly modulate the ecological structure of the intestinal microbiota and is dependent on host genotype and inflammation status.

Animals↗

PubMed2026

Association of IL-10 promoter and IL-12 gene polymorphisms with the risk of symptomatic Helicobacter pylori infection.

BACKGROUND: The host's immune response to Helicobacter pylori (H. pylori) infection is largely determined by its cytokine profile. Genetic variations within crucial immunomodulatory genes, including those for interleukin-10 (IL-10) and interleukin-12 (IL-12), are thought to influence an individual's vulnerability to the infection and its clinical consequences by modifying cytokine production. Nonetheless, research data derived from diverse human populations continue to show inconsistent results. AIM: This case-control analysis sought to examine a potential link between symptomatic H. pylori infection susceptibility in an Iranian population and specific genetic variants in the IL-10 (-1082G > A, -819 C > T) and IL-12 (+ 1188 A > C) genes. METHODS: In this investigation, 68 individuals with confirmed symptomatic H. pylori infection diagnosed by a positive rapid urease test and elevated anti-H. pylori IgG levels exceeding 90 ng/ml via ELISA were enrolled alongside 68 healthy controls. The control group was carefully matched to the patient group based on age, sex, and ethnic background. Genotyping for the IL-10 (-1082G > A, -819 C > T) and IL-12 (+ 1188 A > C) polymorphisms was conducted using the Amplification Refractory Mutation System-PCR (ARMS-PCR) method. To evaluate associations, the distribution of genotypes and alleles between the groups was contrasted using logistic regression, applying additive, dominant, and recessive inheritance models. The strength of any association was expressed as odds ratios (ORs) accompanied by 95% confidence intervals (CIs). RESULTS: The analysis revealed no statistically significant correlations linking the investigated IL-10 and IL-12 gene variants to an increased predisposition for H. pylori infection. A notable methodological observation was the deviation from Hardy-Weinberg equilibrium (HWE) across all studied polymorphisms in the control group. Regarding the IL-10 -1082G > A locus, the AA genotype was associated with a marginally elevated risk estimate; however, this finding was not statistically significant (OR = 3.45, 95% CI: 0.29-41.36; p = 0.327). Likewise, for the IL-12 + 1188 A > C polymorphism, the CC genotype, while more prevalent in the patient cohort, also demonstrated no significant association with infection risk (OR = 1.43, 95% CI: 0.42-4.87; p = 0.567). CONCLUSION: This investigation did not establish a significant link between the specific IL-10 and IL-12 gene variants analyzed and susceptibility to symptomatic H. pylori infection in the studied population. Although minor genetic associations were noted, they lacked statistical significance. Future research with larger sample sizes is required to validate these results and to investigate additional genetic determinants that may affect infection risk.

Humans↗

PubMed2024

Culture Expansion Alters Human Bone Marrow-Derived Mesenchymal Stem Cell Production of Osteoarthritis-Relevant Cytokines and Growth Factors.

PURPOSE: The purposes of this study were to characterize the human bone marrow-derived mesenchymal stem cells (BM-MSCs) production of osteoarthritis-relevant cytokines and growth factors as they are purified and multiplied, a process termed culture expansion, and to compare the immunomodulatory potential of BM-MSCs based on source and medium used for culture expansion. METHODS: BM-MSCs were obtained from iliac crest bone marrow aspirates of 4 healthy donors. These 4 BM-MSC cell lines underwent 4 rounds, or "passages," of the institutional culture expansion protocol, using institutional culture media. The secretory molecules known to play a role in osteoarthritis-related inflammatory immune response, cartilage degradation, and patient symptoms, together called the BM-MSC "secretome," were measured at each passage. Three lines of commercially available BM-MSCs from healthy donors underwent culture expansion by the same protocol, using commercial culture media. The commercial BM-MSCs secretome and the institutional BM-MSCs secretome were compared at each passage. Significance was set at P < .05. RESULTS: Institutional BM-MSCs produced less interleukin-6 at passages 3 (237 ± 113 pg/mL) and 4 (237 ± 113 pg/mL) compared with passages 1 (884 ± 97 pg/mL) and 2 (1071 ± 129 pg/mL; P < .01). Institutional BM-MSCs produced more macrophage inflammatory protein 3-alpha at passage 4 than at passage 1 (106 ± 41 vs 32 ± 7 pg/mL; P < .01). Across passages of culture expansion, institutional BM-MSCs grown on institutional medium expressed more interleukin-6 (P < .001), interleukin-10 (P < .001), interleukin-1 beta (P < .001), tumor necrosis factor alpha (P = .004), and vascular endothelial growth factor C (P = .003) than commercially available BM-MSCs grown on commercial medium. CONCLUSIONS: Culture expansion alters key molecules within the BM-MSC secretome. Additionally, differences in BM-MSC source and culture medium alter the BM-MSC secretome and its immunomodulatory potential. CLINICAL RELEVANCE: This study characterizes the in-vitro changes in BM-MSC secretome during culture expansion based on the cell source and culture medium. It suggests nonequivalence of culture-expanded BM-MSC therapies obtained from different donors using different culture media, even if delivering equivalent numbers of BM-MSCs.

Humans↗

PubMed2025

Circulating inflammatory proteins and osteomyelitis: A bidirectional Mendelian randomization and colocalization analysis.

Circulating inflammatory proteins (CIPs) have been implicated in the progression of osteomyelitis (OM); however, whether these proteins play a causal role or are merely a consequence remains unclear. This study aimed to assess the causal relationships between CIPs and OM using a bidirectional 2-sample Mendelian randomization (MR) approach. MR analyses were performed using genome-wide association study summary statistics for 91 inflammation-related proteins (n = 14,824) and OM (1881 cases and 3,91,037 controls). The inverse variance weighted method was used as the primary analytical approach, supplemented by MR-Egger, weighted median, simple mode, and weighted mode methods. Sensitivity analyses were conducted to evaluate heterogeneity, horizontal pleiotropy, and robustness. Colocalization analysis was applied to identify shared causal variants, and pathway enrichment analysis was used to explore underlying biological mechanisms. Forward MR analysis revealed that elevated levels of tumor necrosis factor-beta (TNF-β) were significantly associated with increased OM risk (odds ratio [OR] = 1.132; 95% confidence interval [CI]: 1.052-1.217; false discovery rate [FDR] = 0.027). Conversely, decreased levels of osteoprotegerin (OR = 0.772; 95% CI: 0.671-0.889; FDR = 0.015) and adenosine deaminase (OR = 0.811; 95% CI: 0.736-0.894; FDR < 0.001) were associated with increased OM risk. Reverse MR analysis identified increased levels of interleukin-15 receptor alpha, C-X-C motif chemokine ligand 1, fms-related tyrosine kinase 3 ligand, interleukin-20, interleukin-10 (IL10), C-C motif chemokine ligand 19, and CXCL6 as being significantly associated with OM susceptibility (all FDR < 0.05). Colocalization analysis provided strong evidence for a shared causal variant between TNF-β and OM (posterior probability for hypothesis 4 = 0.999). Enrichment analyses indicated involvement of implicated proteins in Toll-like receptor signaling and T-helper 17 cell differentiation pathways. This study identified several CIPs - including TNF-β, osteoprotegerin, and adenosine deaminase - as potentially causal in OM development. These findings highlight promising targets for future immunomodulatory therapies aimed at preventing or mitigating osteomyelitis.

Humans↗

PubMed2026

Monocytes Defined by Platelet Interactions and Oxidative Stress Signaling Underlie HIV-Associated Atherosclerosis.

BACKGROUND: Monocytes contribute to atherosclerosis by migrating into inflamed endothelium and differentiating into lipid-laden macrophages. In people living with HIV, chronic inflammation increases atherosclerosis risk, yet the role of specific monocyte subsets remains unclear. We investigated how distinct monocyte populations contribute to vascular pathology in early HIV-associated atherosclerosis. METHODS: We profiled 123 965 circulating monocytes using single-cell RNA sequencing and integrated plasma microparticle proteomics in 32 individuals stratified by HIV and atherosclerosis status. Supervised learning identified cluster- and disease-specific signatures, validated by platelet-monocyte cocultures, reverse transcription-quantitative polymerase chain reaction, bulk RNA sequencing, flow cytometry, and ELISA. RESULTS: Seven monocyte clusters were identified, including a subset characterized by platelet-monocyte complexes. Bulk RNA sequencing of platelet-monocyte cocultures revealed platelet-driven upregulation of genes involved in inflammation, lipid metabolism, oxidative stress, and endothelial adhesion. Platelet-monocyte complex-derived macrophages secreted higher levels of TGF-β (transforming growth factor-β) and IL-10 (interleukin-10), displayed decreased CD14 and increased CD80/CD86 while retaining CD36, and promoted endothelial-to-mesenchymal transition (decreased expression of CDH5 and PECAM1; increased expression of S100A4 and markers of vascular inflammation (ICAM1), VCAM), and IL-6 (interleukin-6), and CCL2 (C-C motif chemokine ligand 2) secretion). Additionally, CD14+ monocytes from HIV+ atherosclerosis-negative and HIV+ atherosclerosis-positive groups showed enhanced ROS-NRF2 (reactive oxygen species-nuclear factor erythroid 2-related factor 2) pathway activities, supported by increased basal and H2O2-induced p90RSK phosphorylation, indicating oxidative stress priming. CONCLUSIONS: Two monocyte clusters contribute independently to vascular immune dysregulation in people living with HIV. Platelet-monocyte complex-derived macrophages promote endothelial dysfunction while adopting a profibrotic cytokine profile. CD14+ monocytes show heightened oxidative signaling and stress responses, consistent with vascular activation. Together, these mechanisms may accelerate atherosclerosis development in HIV, even in the absence of traditional cardiovascular risk factors.

Humans↗

PubMed2026

Candidate biomarker identification for blood stasis syndrome among coronary artery disease patients using the Olink proteomics platform.

OBJECTIVE: To identify candidate biomarkers of blood stasis syndrome (BSS) associated with coronary artery disease (CAD) and explore the underlying inflammatory mechanisms. METHODS: Using the Olink Target 96 Inflammation panel, we identified plasma proteins in a group of 88 patients comprised of healthy controls (HCs), those with CAD and BSS (CAD-BSS), those with CAD without BSS (CAD-non-BSS), and those with BSS without CAD (non-CAD-BSS) (n = 22 in each group). Protein molecules that were specifically expressed in CAD or BSS were identified by differential expression analyses. Subsequently, potential protein biomarkers were identified using least absolute shrinkage and selection operator regression to enable CAD and BSS differentiation. The potential functional mechanisms of identified proteins were then determined by Gene Ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses. RESULTS: Patients with CAD had 31/92 upregulated and 4/92 downregulated proteins compared with those without. Chemokine (C-C motif) ligand 11 (CCL11), CUB domain-containing protein 1, hepatocyte growth factor, sirtuin 2 (SIRT2), eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), CCL25, and tumor necrosis factor (TNF) showed the strongest upregulation (all P <0.0001). Patients with BSS had 8/92 downregulated proteins, specifically CCL28, CCL11, cystatin D, STAM-binding protein, 4E-BP1, matrix metalloproteinase-10, SIRT2, and monocyte chemotactic protein 4, compared with those without (all P < 0.05). The CAD-BSS group had one interleukin-17 (IL-17) upregulated and 10/92 downregulated proteins compared with the CAD-non-BSS group. When compared with the non-CAD-BSS group, the CAD-BSS group had 8 upregulated proteins but only 2 downregulated proteins, namely interleukin-10 receptor subunit alpha (IL-10RA) and TNF-related activation-induced cytokine (both P < 0.05). Totally 10 proteins were identified as potential candidate biomarkers of BSS in CAD patients. After least absolute shrinkage and selection operator regression analysis, two proteins that distinguished between BSS and non-BSS individuals among CAD patients were identified (SIRT2 and 4E-BP1). These proteins are primarily associated with the mechanistic target of rapamycin signaling pathway, which regulates inflammation and oxidative stress. CONCLUSIONS: Results suggest that the inflammatory response and mechanistic target of rapamycin signaling pathway participate in CAD and BSS development, and that SIRT2 and 4E-BP1 are prospective protein biomarkers for patients with CAD and BSS.

Humans↗

PubMed2026

Mechanism of Action of Hedyotis diffusa Extract in a Rat Model of Acute Lung Injury Based on Transcriptomic Analysis.

OBJECTIVE: This study established a rat model of lipopolysaccharide (LPS)-induced acute lung injury (ALI) to evaluate pathological damage, collagen deposition, inflammatory cytokine levels, and key gene/protein expression following Hedyotis diffusa water extract (HDWE) intervention. Combined with ultra-high-performance liquid chromatography-quadrupole Orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS), transcriptomic analysis, and molecular simulation, this study identified the bioactive components of HDWE, evaluated their potential interactions with ALI-related targets, and explored the multi-omics-based protective mechanisms of HDWE. METHODS: Thirty-six Sprague-Dawley (SD) rats were randomly divided into six groups: Control group, ALI group, DXMS group, HDWE-L group (100 mg/kg), HDWE-M group (200 mg/kg), and HDWE-H group (300 mg/kg). Hematoxylin and eosin (H&E) and Masson's trichrome staining were used to evaluate lung pathological changes and collagen deposition. Enzyme-linked immunosorbent assay (ELISA) was used to measure serum tumor necrosis factor-α TNF-α interleukin-1β IL-1β, erleukin-6 (IL-6), and interleukin-10 (IL-10) levels. Transcriptomic analysis identified differentially expressed genes (DEGs), followed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), receiver operating characteristic (ROC), and immune infiltration analyses. Quantitative real-time polymerase chain reaction (qRT-PCR) detected the mRNA expression levels of SPHK1, RELA, and NFKBIA. Immunohistochemistry evaluated the expression of eight hub targets, including endothelin-1 (EDN1), sphingosine kinase 1 (SPHK1), intercellular adhesion molecule 1 (ICAM1), interleukin-17 (IL-17), prostaglandin-endoperoxide synthase 2 (PTGS2/COX-2), NF-κB p65 (encoded by RELA), WT1-associated protein (WTAP), and myeloperoxidase (MPO). UHPLC-Q-Orbitrap HRMS characterized HDWE constituents. Molecular docking analysis was performed between 22 compounds and eight hub targets, followed by 100 ns molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area (MM/PBSA) binding free energy calculations for five core targets. Compared with the control group, the ALI group showed increased levels of TNF-α (86%), IL-1β (107%), and IL-6 (66%), accompanied by a 43% reduction in IL-10 and a 300% increase in lung collagen deposition. All HDWE doses alleviated inflammatory responses, with medium-dose HDWE showing the most pronounced effects. Specifically, medium-dose HDWE increased IL-10 levels by 52% and reduced IL-6, TNF-α, and IL-1β levels by 18%, 22%, and 11%, respectively. Transcriptomic analysis identified 2512 DEGs between the control group and ALI groups, 832 exclusive DEGs between the ALI group and HDWE-M groups, and 876 overlapping DEGs enriched in TNF, IL-17, and NF-κB signaling pathways. The eight-hub-gene diagnostic model achieved an area under the curve (AUC) of 0.969. RELA, SPHK1, and four other hub genes showed positive correlations with Th1, Th17, and neutrophil infiltration. In the ALI group, SPHK1, RELA, and NFKBIA mRNA expression levels were 1.30-, 0.96-, and 0.71-fold of those in the control group, respectively. Compared with the ALI group, high-dose HDWE treatment and low-dose HDWE treatment reduced SPHK1 expression to 0.62- and 0.57-fold, respectively, and increased NFKBIA expression to 1.68- and 1.58-fold, respectively. High-dose HDWE treatment reduced RELA expression to 0.43-fold. The expression levels of inflammation-related proteins were increased in the ALI group and were reduced after HDWE treatment. Twenty-two HDWE components were identified, 16 of which met the docking criteria. Asperulosidic acid exhibited favorable predicted binding affinities with all eight targets, with calculated binding free energies of -14.74, -14.92, -17.58, -23.04, and -16.10 kcal/mol for MPO, IL-17, NF-κB p65, PTGS2/COX-2, and SPHK1, respectively. CONCLUSIONS: This study provides systematic in vivo pharmacodynamic and in silico component-target evidence regarding the protective effects of HDWE against LPS-induced ALI. HDWE treatment increased NFKBIA expression and reduced SPHK1, RELA, and multiple inflammatory protein levels, suggesting that HDWE may regulate the IL-17/NF-κB-associated inflammatory network, although direct causal relationships require further validation. Asperulosidic acid may represent a key bioactive component with broad target-binding potential. This study was limited by the use of an LPS-induced rat ALI model without gene knockout or target inhibitor validation; therefore, further functional experiments are required to confirm the proposed regulatory mechanisms.

Hedyotis diffusa↗

PubMed2026

ADAM10's combined influence on the diagnostic usefulness of IL 22, IL 10, IL-17 A, and IL-17D in autism spectrum disorders: Predicted role on gut leakiness as co-morbidity.

Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder with increasing global prevalence but a lack of reliable diagnostic biomarkers. Emerging evidence suggests that immune dysregulation, gut-brain axis dysfunction, and increased intestinal permeability play key roles in ASD pathophysiology. This study investigated the combined diagnostic value of ADAM10 and cytokines (IL-10, IL-22, IL-17 A, and IL-17D). Multivariable logistic regression produces an improved ROC curve that improves diagnostic accuracy over individual markers by combining numerous predictors into a single risk score (linear predictor). The technique, which frequently raises individual marker AUCs, entails modelling a binary result, calculating the probability, and visualizing ROC based on the projected probabilities. In this case-control study, plasma levels of ADAM10, IL-10, IL-22, IL-17 A, and IL-17D were measured in 37 male children with ASD and 37 age-matched controls. Group comparisons, correlation analyses, and receiver operating characteristic (ROC) curve analyses, including combined ROC models, were performed. ADAM10, IL-22, and IL-17 A levels were significantly reduced in children with ASD compared to controls, whereas IL-10 and IL-17D showed no significant differences. ADAM10, IL-17 A, and IL-22 demonstrated good diagnostic performance, with AUC values of 0.886, 0.855, and 0.812, respectively. In contrast, IL-10 and IL-17D showed poor discriminatory ability, with AUC values of 0.524 and 0.599, respectively. Combined ROC analysis markedly improved diagnostic accuracy, with all panels including ADAM10 achieving AUC values above 0.90, and some reaching as high as 0.988, with high sensitivity and specificity. The combination of ADAM10 with selected cytokines significantly enhances diagnostic performance compared to individual markers, supporting a link between immune dysregulation, barrier dysfunction, and gut permeability in ASD.

Humans↗

PubMed2026

Localized PD-1 CAR T therapy reprograms neuroinflammation.

B cell-depleting therapies are effective in multiple sclerosis (MS), yet some patients relapse, underscoring the need for more precise interventions. To identify new therapeutic targets, we generated a single-cell RNA sequencing (scRNA-seq) atlas of cerebrospinal fluid (CSF), brain, and blood from non-inflammatory controls and patients with MS or other neuroinflammatory diseases. We found disease-associated enrichment of class-switched immunoglobulin G+ (IgG+) B cells and plasma cells in MS CSF. Unbiased analysis identified a rare disease-enriched subset of activated, T cell receptor (TCR)-restricted, PD-1+ T follicular helper-like cells with B cell-recruiting features. To target this population, we developed PD-1-directed chimeric antigen receptor (CAR) T cells that selectively depleted pathogenic PD-1+ CD4 T cells and locally released IL-10. This strategy attenuated central nervous system (CNS) inflammation, reprogrammed the local immune milieu, and improved clinical outcomes across murine neuroinflammation models. These findings define a CNS-localized adaptive immune circuit in MS and nominate programmable PD-1 CAR T cells as a strategy to disrupt it.

Animals↗

PubMed2025

Modulation of Mettl5 alleviates airway allergy by regulating the epigenetic profile of M2 macrophages.

M2 macrophages (M2 cells) are known to be involved in both Th2 responses and immune regulation. However, the underlying mechanisms remain unclear. Functional abnormalities in macrophages are associated with airway allergy (AA). The objective of this study was to investigate the role of methyltransferase-like 5 (Mettl5) in macrophages and its potential to alleviate AA. In this study, an airway allergy (AA) mouse model was established using dust mite extracts (DME) as the specific antigen. M2 cells were collected from mice with and without AA. The role of Mettl5 in modulating the immune activities of M2 cells was assessed using both epigenetic and immunological approaches. We found that Mettl5 levels were elevated in airway M2 cells from mice with AA. The presence of Mettl5 in airway M2 cells was positively correlated with airway Th2 polarization in these mice. Airway M2 cells from AA mice exhibited impaired immune-suppressive function, which was resolved by ablating the Mettl5 gene in macrophages. Mettl5 was responsible for the hypermethylation of the Il10 promoter in airway M2 cells of AA mice. Exposure to DME induced Mettl5, which in turn recruited USP21 to deubiquitinate GATA3, thereby boosting IL-4 expression in M2 cells. Inhibiting Mettl5 restored the immune-suppressive capacity of airway M2 cells and mitigated experimental AA. In conclusion, Mettl5 plays a critical role in subverting the immune-regulatory capacity and enhancing IL-4 expression in M2 cells. Inhibition of Mettl5 can mitigate experimental AA by restoring the immune-regulatory functions of M2 cells.

Animals↗

PubMed2024

Exclusive enteral nutrition initiates individual protective microbiome changes to induce remission in pediatric Crohn's disease.

Exclusive enteral nutrition (EEN) is a first-line therapy for pediatric Crohn's disease (CD), but protective mechanisms remain unknown. We established a prospective pediatric cohort to characterize the function of fecal microbiota and metabolite changes of treatment-naive CD patients in response to EEN (German Clinical Trials DRKS00013306). Integrated multi-omics analysis identified network clusters from individually variable microbiome profiles, with Lachnospiraceae and medium-chain fatty acids as protective features. Bioorthogonal non-canonical amino acid tagging selectively identified bacterial species in response to medium-chain fatty acids. Metagenomic analysis identified high strain-level dynamics in response to EEN. Functional changes in diet-exposed fecal microbiota were further validated using gut chemostat cultures and microbiota transfer into germ-free Il10-deficient mice. Dietary model conditions induced individual patient-specific strain signatures to prevent or cause inflammatory bowel disease (IBD)-like inflammation in gnotobiotic mice. Hence, we provide evidence that EEN therapy operates through explicit functional changes of temporally and individually variable microbiome profiles.

Crohn Disease↗

PubMed2026

Defined human Clostridia consortia reverse colitis via dual effects of tryptophan metabolites on microbiota and immunity.

Microbial dysbiosis and disrupted mucosal immune homeostasis are integrally involved in the pathogenesis of inflammatory bowel diseases (IBDs). Live biotherapeutic products (LBPs) offer a potential therapeutic strategy to restore beneficial microbes and mitigate disease. We investigated the therapeutic efficacy of 2 LBPs, human Clostridia consortia 17-mix and 11-mix, by treating established colitis in murine models. Both LBPs exhibited therapeutic effects in T cell-mediated chronic colitis models induced by human microbiota and in pathobiont-driven gnotobiotic colitis models established with combinations of IBD-relevant human-derived strains. Metagenomic and metabolomic analyses elucidated mechanisms that go beyond established functions driven by short-chain fatty acids (SCFAs) and interleukin (IL)-10-producing regulatory T cells. Notably, LBPs exerted therapeutic effects by directly inhibiting resident pathobionts and through IL-10-independent activation of host anti-inflammatory aryl hydrocarbon receptor (AhR) pathways by bacterial tryptophan metabolites. These results elucidate SCFA- and IL-10-independent protective mechanisms exerted by defined resident bacterial strains that are depleted in IBD dysbiosis.

Animals↗

PubMed2026

A transient, B cell-targeted tolerance switch using nanoparticles loaded with metabolizable AhR agonists for antigen-specific immune regulation.

Achieving antigen-specific immune tolerance without systemic immunosuppression remains a major challenge in biomaterial-based immunotherapy. Here, we report a simple nanoparticle (NP)-based platform that enables a transient, B cell-targeted tolerance switch. NPs encapsulating metabolizable aryl hydrocarbon receptor (AhR) agonists-FICZ or ITE-preferentially accumulate in splenic marginal zone B cells and convert them into IL-10-producing regulatory B cells (Bregs). This study provides the first in vivo evidence that Bregs can directly present antigen and induce regulatory T cells (Tregs), establishing a NP-controlled Breg-Treg pathway. These Bregs promote antigen-specific Tregs expansion only when co-exposed to antigen, establishing time-gated, antigen-restricted immune regulation. By exploiting the rapid metabolism of AhR agonists, this system provides precise temporal control of tolerance induction while preserving vaccine responses. In mouse models, co-administration of FICZ-containing NP with antigen suppressed anti-drug antibody formation and ameliorated allergic inflammation. This NP platform demonstrates a strategy for safe, antigen-specific immunomodulation and offers a clinically adaptable framework for allergy and biotherapeutic tolerance.

Animals↗

PubMed2026

Genetic diversity of Collaborative Cross mice implicates FFAR3 as a target for ILC2 anti-inflammatory reprogramming.

Pulmonary group 2 innate lymphoid cells (ILC2s) are key drivers of Type 2 inflammation in diseases like asthma, yet the molecular mechanisms regulating their function are incompletely understood. Using the genetically diverse Collaborative Cross (CC) mouse panel, we mapped a quantitative trait locus (QTL) that governs ILC2 prevalence in the lung after aeroallergen exposure. This QTL induces a large population of ILC2s in the lung that are resistant to activation and have diminished Type 2 effector function. We identified free-fatty acid receptor 3 (Ffar3) as a gene responsible for this effect and demonstrated that FFAR3 signaling reprograms ILC2s to an anti-inflammatory state by promoting their survival, reducing Type 2 cytokine production, and enhancing IL-10 expression. This anti-inflammatory state is dependent on IL-2 signaling, is characterized by decreased ST2 expression, and is distinct from previously described IL-10-producing ILC2 phenotypes. FFAR3-dependent reprogramming is mediated by epidermal growth factor receptor (EGFR) upregulation, and FFAR3's anti-inflammatory effect is partially conserved in human ILC2s.

Animals↗

PubMed2026

A stromal platform for robust expansion of functional IL-10-producing B cells for immune regulation.

IL-10-producing B cells exert immunosuppressive effects, yet their low abundance and poor in vitro viability have limited their therapeutic application. Here, we developed a stromal coculture system using MS5 cells engineered to express human CD40L, BAFF, and IFN-β1 (MS5-3F, for "3 factors"), which enables robust induction and greater than 1000-fold expansion of human IL-10-producing B cells. The expanded cells showed phenotypic and transcriptional profiles characteristic of unswitched (IgM+) plasmablasts and potently suppressed CD4+ T cell proliferation in an IL-10-dependent manner. MS5-3F-expanded B cells also increased the frequency of regulatory T cells in vitro, an effect that was not abrogated by IL-10/IL-10R blockade, suggesting contributions from additional mechanisms. IL-10 production originated predominantly from naive B cells, rather than memory B cells. Furthermore, B cells from patients with systemic lupus erythematosus, despite impaired IL-10 production under conventional conditions, were efficiently differentiated into IL-10-producing B cells using this system. The expanded cells showed minimal IgG-secreting output. Our platform offers a scalable strategy for generating human regulatory B cells, laying the foundation for B cell-based immunotherapies.

Humans↗

PubMed2026

Levels of circulating kidney injury markers and IL-10 identify non-critically ill patients with COVID-19 at risk of death.

BACKGROUNDAfter identifying 2 immunomarkers of acute injury, KIM-1 and LCN2, in all kidney biopsies from 31 patients with COVID-19 pneumonia and de novo kidney dysfunction, we investigated whether circulating markers of kidney epithelial injury are common in patients with laboratory-confirmed COVID-19 who require oxygen support but do not have critical illness.METHODSWe studied 196 patients admitted to 15 hospitals with moderate to severe pneumonia who were enrolled in 2 independent randomized clinical trials. We measured 41 immune mediators and markers of kidney and endothelial injury in peripheral blood in these patients within 24 hours of randomization.RESULTSWe constructed a generalized linear CORIMUNO model combining serum levels of KIM-1, LCN2, IL-10, and age at hospital admission that showed high discrimination for mortality (derivation cohort: AUC = 0.82, 95% CI: 0.73-0.92; validation cohort: AUC = 0.83, 95% CI: 0.74-0.92). An early rise in circulating kidney injury markers, in the absence of acute kidney injury criteria, was markedly associated with the risk of developing a severe form of COVID-19 and death within 3 months.CONCLUSIONThe CORIMUNO score may be a helpful tool for risk stratification, and for the first time to our knowledge, it identifies the overlooked impact of subclinical kidney injury on pneumonia outcomes.TRIAL REGISTRATIONClinicalTrials.gov NCT04324047, NCT04324073, and NCT04331808.FUNDINGThis research was funded by the French Ministry of Health, Programme Hospitalier de Recherche Clinique (PHRC COVID-19-20-0151, PHRC COVID-19-20-0029), Fondation de l'Assistance Publique Hôpitaux de Paris (Alliance Tous Unis Contre le Virus), Assistance Publique Hôpitaux de Paris, and grants from the Fondation pour la Recherche Médicale (FRM) (REA202010012514) and Agence Nationale de Recherches sur le Sida and emerging infectious diseases (ANRS) (ANRS0147) from the VINTED sponsorship.

Humans↗

PubMed2026

Natural killer (NK) cells with downregulated activating receptors and IL-10 production promote Trypanosoma cruzi T-cell responses in subjects in the Chronic phase of Trypanosoma cruzi infection: An exploratory immunological analysis.

BACKGROUND: Subjects with chronic Chagas disease and no signs of heart disease exhibit decreased NKp46 expression, high CD57 expression, and IL-10 production by NK cells. This study provides a detailed characterization of the phenotype and function of NK cells according to the severity of heart disease, and evaluates how these changes following treatment with benznidazole, as well as their association with Trypanosoma cruzi-specific T-cell responses. METHODS: The phenotype and function of NK cells in a cohort of 51 subjects infected with Trypanosoma cruzi and exhibiting varying degrees of heart disease were evaluated using high-dimensional flow cytometry and Boolean gating analysis. ELISPOT assays were performed to measure IFN-γ and IL-2 production in response to T. cruzi antigens, using CD56, CD4 and CD8-depleted PBMC. RESULTS: In contrast to individuals without heart disease, those with advanced cardiomyopathy have an increased number of NK cells that express the activating receptors NKp46 and CD16, as well as the differentiation marker CD57. NK cells in subjects with advanced cardiomyopathy were also found to be enriched in CD56+CD107+granzyme B+TNF-α+ cells and depleted of CD56+IL-10+ cells. The function of NK cells shifted towards monofunctionality in subjects with declining T. cruzi-specific antibodies following treatment with benznidazole. Eliminating CD56+ cells significantly decreased the number of IFN-γ-producing cells in response to T. cruzi. CONCLUSIONS: In chronic T. cruzi infection, NK-cell function may be balanced by the downregulation of activating receptors and IL-10 production, However, parasite persistence may desensitize the regulation of NK activating receptors, enabling NK cells to exert a potent polyfunctional cytotoxicity that potentially induce tissue damage.

Humans↗

PubMed2024

Acute strength exercise training impacts differently the HERV-W expression and inflammatory biomarkers in resistance exercise training individuals.

BACKGROUND: Human Endogenous Retroviruses (HERVs) are fossil viruses that composes 8% of the human genome and plays several important roles in human physiology, including muscle repair/myogenesis. It is believed that inflammation may also regulate HERV expression, and therefore may contribute in the muscle repair, especially after training exercise. Hence, this study aimed to assess the level of HERVs expression and inflammation profile in practitioners' resistance exercises after an acute strength training session. METHODS: Healthy volunteers were separated in regular practitioners of resistance exercise training group (REG, n = 27) and non-trained individuals (Control Group, n = 20). All individuals performed a strength exercise section. Blood samples were collected before the exercise (T0) and 45 minutes after the training session (T1). HERV-K (HML1-10) and W were relatively quantified, cytokine concentration and circulating microparticles were assessed. RESULTS: REG presented higher level of HERV-W expression (~2.5 fold change) than CG at T1 (p<0.01). No difference was observed in the levels of HERV-K expression between the groups as well as the time points. Higher serum TNF-α and IL-10 levels were verified post-training session in REG and CG (p<0.01), and in REG was found a positive correlation between the levels of TNF-α at T1 and IL-10 at T0 (p = 0.01). Finally, a lower endothelial microparticle percentage was observed in REG at T1 than in T0 (p = 0.04). CONCLUSION: REG individuals exhibited a significant upregulation of HERV-W and modulation of inflammatory markers when compared to CG. This combined effect could potentially support the process of skeletal muscle repair in the exercised individuals.

Humans↗