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Glioblastoma (GBM) poses unique challenges to immunotherapy, owing to its low tumor mutational burden, profound antigenic heterogeneity, and highly immunosuppressive microenvironment. Observations of tumor-infiltrating lymphocytes (TILs) in human GBM differ from those in syngeneic orthotopic murine models: whereas TILs in several widely used murine glioma models display an abundance of exhausted T cells, patient tumors are enriched for clonally expanded granzyme K⁺ T cells of uncertain function. We review the current understanding of the brain tumor immunity cycle in GBM, highlight the translational implications of TIL biology, and evaluate emerging TCR-based approaches, including adoptive TILs transfer, neoantigen vaccines, and engineered receptors. A refined focus on identifying and harnessing tumor-selective T cells may enable more rational, personalized immunotherapies for GBM.
Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by a near-universal presence of KRAS mutations and limited responsiveness to immunotherapy. Biologic heterogeneity among KRAS subtypes may shape tumor immunobiology and treatment resistance. Methods: We evaluated 109 patients with advanced PDAC treated in early-phase trials between August 2014 and August 2023. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and Cox proportional hazard models were used to assess the clinical and molecular predictors of survival. Results: Among the 109 patients, 64% harbored KRAS mutations, 18% were KRAS wild type, and 17% had an unknown KRAS status. The median age was 65 years, and 83% had liver metastases. Among the KRAS-mutant tumors, subtype distribution was G12D (46%), G12V (31%), G12R (13%), and other variants (10%). Immunomodulatory agents were administered to 39% of the patients, most commonly in the first-line setting (49%). The median OS and PFS for the entire cohort were 5.65 and 2.73 months, respectively. The restricted mean OS (7.54 vs. 8.65, p = 0.53) and PFS (3.82 vs. 4.24, p = 0.70) did not differ between patients with KRAS mutants and wild-type KRAS. Among patients with KRAS mutations, receipt of immunomodulatory therapy was associated with shorter OS compared with those who did not receive immunomodulatory therapy, with the strongest association observed in the KRAS G12D subgroup. This pattern was not observed in KRAS wild-type tumors. On univariate analysis, immunomodulatory therapy exposure, number of prior treatment lines, and presence of liver metastases were each associated with inferior OS. On multivariable analysis, immunotherapy exposure demonstrated a non-significant trend toward inferior OS (hazard ratio [HR] 1.61, 95% Cl 0.98-2.66; p = 0.06), while the other variables remained independently associated with worse OS, suggesting confounding in the unadjusted association between immunomodulatory therapy and survival. Conclusions: Among patients with KRAS-mutant PDAC-particularly those with G12D-receipt of immunomodulatory therapy in early-phase trials was associated with shorter OS in this exploratory analysis. These findings should be considered hypothesis-generating and require validation in prospective, KRAS-subtype-informed studies.
The use of immune checkpoint inhibitors (ICIs) is expanding in the treatment of a variety of cancer types; however, treatment with ICIs may result in off-target kidney inflammation in 3-5% of patients, most commonly acute interstitial nephritis (AIN). There is a significant unmet need for noninvasive diagnostic tools to facilitate accurate and timely diagnosis, and for targeted therapeutic strategies to more specifically block inflammation in ICI-AIN. The most promising emerging noninvasive diagnostic strategies include novel urinary biomarkers such as C-X-C motif ligand 9 (CXCL9), tumor necrosis factor alpha (TNF-α), interleukin 5 (IL-5), and Fas. There are increasing data to support treatment strategies that may better preserve the antitumor effect of ICIs, including the use of infliximab, as well as shorter corticosteroid courses. Novel biomarkers have shown great potential, although further studies will be required for validation. Improving scientific understanding of the underlying immunobiology in ICI-AIN and other ICI toxicities may uncover new pathways amenable to more specific therapeutic targeting, such as TNF-α. General nephrologists should be aware of recent advances in biomarker discovery and second-line immunosuppressives, given the increasingly widespread use of ICIs.
Triple-negative breast cancer is an aggressive and heterogeneous breast cancer subtype for which immune checkpoint inhibitors combined with chemotherapy have improved outcomes in selected patients. However, primary and acquired resistance remain common, underscoring the need to identify extrinsic, modifiable determinants of antitumor immunity. Increasing evidence indicates that the gut and tumor-associated microbiota shape systemic and intratumoral immune tone and influence the efficacy of cancer therapies. Beyond microbial composition, microbiota-derived metabolites-including short-chain fatty acids, indole-tryptophan derivatives, bile acids, polyamines, and other small molecules-can act as functional mediators linking microbial ecology to immune-cell programming and tumor biology. These metabolites modulate dendritic cell function, T-cell priming and fitness, myeloid polarization, inflammatory set points, and metabolic pathways within the tumor microenvironment, thereby potentially enhancing or constraining responses to chemoimmunotherapy. Importantly, while some studies propose intratumoral microbial effects, most clinically actionable evidence currently supports systemic gut-derived metabolites and immune tone modulation that secondarily shapes the TNBC tumor microenvironment. In this review, we synthesize current knowledge on (i) the immunobiology of triple-negative breast cancer (TNBC) relevant to microbiota-driven modulation, (ii) mammary and gut microbiome features reported in TNBC, and (iii) mechanistic pathways through which microbial metabolites may regulate antitumor immunity and immune checkpoint inhibitors (ICI) sensitivity. We also discuss methodological considerations for integrating microbiome profiling with metabolomics and immune phenotyping and evaluate emerging opportunities to leverage microbiota-derived metabolites as biomarkers and therapeutic targets. Finally, we highlight translational strategies-including diet, pre/probiotics, antibiotic stewardship, fecal microbiota transplantation, and metabolite-centric ("postbiotic") approaches-and outline priorities for TNBC-focused, prospective multi-omics studies to move from associative signatures toward actionable interventions.
Acute myocardial infarction(AMI)is an important type of cardiovascular disease, which seriously threatens the lives of humans. In order to help patients receive timely clinical treatment and improve their survival rates, it is necessary to screen out related molecules in advance. To this end, we applied bioinformatics methods and machine learning algorithms to find possible biomarkers associated with AMI. When considering possible connections with dynamics of immune cells activation. Based on the RNA-seq results, differential expression analysis was performed followed by WGCNA to identify stably changed genes. The KEGG and GO enrichment analyses revealed that the identified genes are mainly related with inflammatory response, immune processes, apoptosis and immunomodulation. In our PPI network, some hub genes (e.g., FOS, JUN, TNF, IL1B, TLR2) were located in the center of the whole network. We found strong associations between the major genes and their interaction effects, we developed a predictive model for diagnosis using an artificial intelligence algorithm as follows: suggesting a substantially increased discriminative performance for AMI with the 4 hub genes NFKBIA, FCER1G, CD36 and ICAM1. The model achieved a high AUC score of 0.924. External validation based on an independent single-cell sequencing dataset demonstrated that NFKBIA, FCER1G, and ICAM1 displayed consistent expression patterns in both the training and test cohorts, with the highest expression levels observed in cardiomyocytes. Accordingly, these three genes may serve as reliable biomarkers for AMI and are closely associated with the distribution of immune cells.
Intestinal epithelial cells (IEC) are the primary cell type in direct contact with stimuli from the luminal microbiota, playing a critical role in host-microbe interactions. However, how IECs communicate with underlying immune cells to maintain homeostasis remains poorly understood. In addition, the mechanisms by which IECs sense microbiota-derived stimuli to initiate this crosstalk are not yet fully understood. Here, we demonstrate that oral administration of the gut microbiota metabolite butyrate induces sustained IL-10 production in CD4⁺ T cells, conferring long-lasting protection against intestinal inflammation even after treatment withdrawal. This persistent immunoregulatory effect is also observed in germ-free mice, indicating the establishment of a butyrate-conditioned intestinal environment. By metabolomic profiling, we identify N1-acetylspermidine as a metabolite contributing to the IL-10-inducing activity of butyrate-treated IEC-conditioned medium. Mechanistically, butyrate induces sustained transcriptional and epigenetic activation of the acetylpolyamine biosynthetic enzyme Sat1 in IECs, which catalyzes the acetylation of spermidine to generate N1-acetylspermidine, and this activation persists after butyrate withdrawal. Together, our findings reveal a mechanism by which butyrate sensing establishes persistent crosstalk between IECs and T cells, thereby maintaining intestinal immune tolerance through epigenetic regulation and reprogramming of epithelial metabolism.
High-riding vertebral artery (HRVA) at C2 is more prevalent in patients with rheumatoid arthritis (RA) than in the general population, but its clinical significance remains unclear. Recent evidence in non-RA individuals suggests that unilateral HRVA may contribute to atlantoaxial joint degeneration (AAJD) through asymmetric mechanical stress. This study investigated whether unilateral HRVA is similarly associated with the progression of AAJD in RA. We retrospectively analyzed 336 RA patients from the single institutional cohort who underwent CT scans, including C1-C2, between 2011 and 2024. HRVA was defined as a C2 internal height < 2 mm and/or isthmus height < 5 mm. Morphological parameters (C1 lateral mass height, C1/2 coronal inclination, and C1/2 relative rotation angle) and AAJD grades were evaluated. Logistic regression was used to identify factors associated with moderate-to-severe AAJD (grade ≥ 2). HRVA was observed in 147 patients (116 unilateral). Compared with patients without HRVA, those with unilateral HRVA had longer RA duration (17.5 vs. 12.9 years, p < 0.01) and higher ACPA positivity (78.8% vs. 66.9%, p < 0.05), but no differences in disease activity or medication use. Moderate-to-severe AAJD was significantly more frequent in the unilateral HRVA group (62.9% vs. 42.3%, p < 0.001). Multivariate analysis identified older age, longer RA duration, and unilateral HRVA as independent risk factors for AAJD. These findings indicate that unilateral HRVA is independently associated with atlantoaxial facet joint degeneration in patients with RA in addition to aging and disease duration, suggesting a role of asymmetric mechanical loading in cervical joint pathology.
Dosage compensation (DC) in Drosophila equalizes X chromosome-linked gene expression via the male-specific lethal complex, which acetylates histone 4 lysine-16 on the male X chromosome. How DC is established during early embryogenesis remains obscure, largely due to the difficulty of obtaining sufficient sex-specific material at early embryonic stages. Here, we developed a high-throughput embryo sorting strategy and combined newly synthesized RNA-sequencing and RNA polymerase II (Pol II) profiling to investigate the mechanisms underlying the onset of DC in vivo. We found that changes in transcription initiation occur before detectable differences in transcriptional pausing or elongation and represent the primary determinant of enhanced mRNA output during DC establishment. It had hitherto been unclear whether DC establishment and maintenance exerted similar or distinct effects on transcriptional kinetics. Extending genome-wide profiling to S2 cells, we uncovered Pol II initiation as a general principle underlying both inception and perpetuation of DC-driven transcriptional up-regulation.
Measurable residual disease (MRD) is a key prognostic marker in acute myeloid leukemia (AML), but its significance in patients treated with azacitidine and venetoclax (AZA/VEN) outside clinical trials remains unclear. We retrospectively analyzed 220 newly diagnosed AML patients from the French VENAURA registry who achieved composite complete remission and underwent MRD evaluation by multiparametric flow cytometry (MFC, LAIP/LSC) and/or NPM1 RT-qPCR. Cumulative MRD negativity was achieved in 62-67% of patients. Attaining MRD negativity at any time was strongly associated with superior overall survival (OS: 31.3 months vs 15.7 months (HR = 0.47) for LAIP, not reached vs 10.8 months (HR = 0.38) for NPM1; all p < 0.001) and lower cumulative incidence of relapse. Dual LAIP/LSC negativity (NEG/NEG) conferred the best outcomes compared to NEG/POS (HR = 0.36, p = 0.02), POS/NEG (HR = 0.24, p < 0.001) and POS/POS (HR = 0.26, p = 0.26) status. Importantly, MRD response mitigated the adverse prognostic impact of ELN 2024 intermediate/poor risk, with MRD-negative patients achieving outcomes comparable to favorable-risk cases. MRD kinetics (early vs late responders) did not affect survival, while G-CSF use improved MRD conversion and OS. In real-world AZA/VEN-treated AML, achieving deep MRD negativity, by MFC or NPM1 RT-qPCR, emerges as the dominant prognostic determinant, overriding baseline risk and supporting its integration into response-adapted strategies.
Amino acid metabolism has been increasingly recognized as a central determinant of obesity and insulin resistance, yet the specific contributions of individual amino acids require further clarification. The aim of the study was to detect relationships between serum amino acid concentrations and metabolic parameters in overweight and obese individuals. Amino acid concentrations were measured in 50 individuals classified as normal weight, overweight, or obese, and were analyzed using principal component analysis (PCA), K-means clustering, multiple linear regression, and Random Forest models. Obese individuals exhibited markedly elevated levels of branched-chain amino acids (BCAAs: valine, isoleucine, leucine) and glutamic acid, accompanied by reduced concentrations of serine, glycine, and glutamine, compared with normal weight participants. PCA revealed that the first component, which explained 35.5% of the total variance, was driven primarily by BCAAs, serine, and glutamine, while the second component, accounting for 9.5% of variance, was influenced by threonine, tryptophan, and asparagine. The multiple linear regression model explained 89.6% of the variance in HOMA-IR (R2 = 0.896, p < 0.001), with isoleucine emerging as the strongest positive predictor (p < 0.001), valine and leucine showing additional significant associations (p = 0.035), and tyrosine demonstrating a significant negative association (p = 0.039), while proline was not significant. The Random Forest model predicting insulin resistance achieved robust cross-validated performance (R2 = 0.86 ± 0.06), with valine, isoleucine, and leucine accounting for the majority of predictive importance, followed by tyrosine and glutamine. Together, these findings demonstrate that amino acid profiling provides powerful discriminatory and predictive capacity for insulin resistance and obesity. BCAAs consistently emerged as the most important predictors across complementary analytical frameworks, confirming their central role in metabolic dysregulation, while glycine appeared to exert a potential protective effect. The identification of a metabolically overweight subgroup underscores the heterogeneity of the overweight state and highlights the utility of amino acid profiling for early risk stratification and the development of targeted interventions.
Accumulating evidence indicates that bone marrow transplantation induces tolerance against simultaneously transplanted allogeneic organs; however, the mechanistic aspects of this phenomenon are less understood. It is known that early T-cell progenitors (ETPs) generate myeloid cells, such as dendritic cells (DCs) and macrophages, as well as T cells in the thymus. Here, we speculate that myeloid cells produced by ETPs may act as allogeneic antigen-presenting cells (APCs) and play an important role in T-cell selection, thereby contributing to tolerance induction. To elucidate the contribution of ETP-derived APCs in T-cell selection, we sorted and cultured ETPs (CD4-CD8-c-Kit+CD25- cells) in a combined ex vivo and in vivo system to generate T cells and APCs simultaneously, followed by a flow cytometric analysis of Vβ T-cell receptor (TCR). To evaluate the importance of ETP-derived APC in allogeneic tolerance, we transplanted ETP-reconstituted fetal thymus to athymic nude mice and performed skin transplantation. Flow cytometric analysis of the ETP culture showed the presence of CD11c+ major histocompatibility complex class II+ ETP-derived DCs, and the T cells generated in the culture showed a low frequency of specific TCR Vβ repertoire, suggesting clonal deletion. ETP-derived DCs also induced the deletion of a specific Vβ TCR repertoire in the in vitro coculture. Furthermore, nude recipients of ETP-reconstituted fetal thymus showed long-term allogeneic skin graft survival while third-party skin was rapidly rejected. The presence of ETP-derived APC is related to the deletion of specific Vβ TCR repertoire and skin allograft survival. By eliminating donor-reactive T-cell clones, ETPs may contribute to allograft tolerance.
DCAF11 is a substrate receptor of the Cullin-RING ligase 4 (CRL4) ubiquitin ligase complex and an emerging effector supporting targeted protein degradation. DCAF11 exists as two major isoforms, but their functional differences remain incompletely understood. Here, we show that DCAF11 isoforms 1 and 2 assemble into CRL4 complexes with similar efficiency and exhibit largely overlapping endogenous substrate profiles, including proteins implicated in electrophile detoxification. In contrast, they differ in their compatibility with small-molecule degraders: covalent PROTACs engage both isoforms, whereas a non-covalent molecular glue selectively utilizes isoform 1. These findings reveal isoform-dependent control of protein degradation and highlight opportunities for isoform-selective targeting.
Severe asthma remains a major unmet clinical challenge due to its marked immunological heterogeneity and the limited efficacy of current therapies in non-Type 2 inflammatory endotypes. Although biologics targeting IL-4, IL-5, and IL-13 have significantly improved outcomes in eosinophilic asthma, therapeutic options for Type 1 and mixed inflammatory phenotypes remain inadequate. The failure of anti-TNF-α therapies highlighted critical translational barriers including cytokine redundancy, insufficient endotype stratification, and systemic safety concerns, thereby reshaping the direction of respiratory immunopharmacology toward precision-guided intervention strategies. This review critically examines the immunobiology of Type 1 and Type 2 inflammation, evaluates the mechanistic and clinical lessons derived from anti-TNF-α trials, and discusses emerging therapeutic platforms including nanobodies, RNA-based therapeutics, gene-editing technologies, cell-based immunotherapies, and advanced pulmonary delivery systems. Furthermore, the review highlights the growing role of multi-omics biomarkers, microbiome profiling, and artificial intelligence in enabling adaptive and personalized asthma management. Collectively, these advances support a transition from generalized cytokine blockade toward integrated immune-network modulation for severe asthma across diverse inflammatory endotypes.
This study aimed to develop a set of quality indicators (QIs) based on the 2025 European Alliance of Associations for Rheumatology (EULAR) recommendations for systemic lupus erythematosus with kidney involvement and explore their association with disease outcomes. A modified Research and Development and University of California, Los Angeles appropriateness method was used. In 2 voting rounds, 23 experts rated candidate QIs for validity and feasibility. Median ratings and agreement were calculated, leading to a core QI set. Adherence to recommended care from healthcare providers was assessed at both QI and patient levels in a single tertiary centre contemporary lupus nephritis (LN) cohort (n = 130). High adherence was defined as ≥80%. Associations between adherence to QIs, damage accrual, and renal flares were explored. A total of 17 QIs were developed across 4 domains: diagnosis, treatment, monitoring, and pregnancy. High adherence was observed for kidney biopsy, hydroxychloroquine use, maintenance immunosuppression, therapy switching in persistent or relapsing disease, renin-angiotensin system inhibitor use, remission before kidney transplantation, and pregnancy-related QIs. Combination immunosuppressive therapy as initial treatment had low adherence (10.7%), reflecting practice patterns preceding publication of the recommendations. High per-patient adherence was associated with lower odds of damage accrual (increase in Systemic Lupus International Collaborating Clinic Damage Index; odds ratio: 0.29, 95% CI: 0.13-0.62) and fewer renal flares, although the latter association was not statistically significant. These QIs may serve as a structured framework for implementing the 2025 EULAR recommendations for LN. Higher adherence was associated with reduced damage accrual in a tertiary centre cohort, but results need validation in diverse clinical settings.
Concentrated growth factor (CGF) is rich in growth factors and complement proteins like C3a and C5a, showing promise for enhancing tissue regeneration. This study explores the regulatory effects of recombinant C3a/C5a proteins on the osteogenic differentiation of PDLSCs in an inflammatory microenvironment and their potential association with the Wnt/β-catenin pathway. P-PDLSCs were generated by treating PDLSCs with IL-1β (5 ng/mL) and TNF-α (10 ng/mL) for 24 h. Subsequently, P-PDLSCs were treated with C5a and C3a, followed by evaluation of cell viability and early osteogenic differentiation capacity (ALP activity). To investigate the underlying mechanism, cells were treated with the Wnt/β-catenin pathway inhibitor, XAV939, either alone or combined with C3a/C5a. Cell viability, ALP activity, and the mRNA and protein levels of AKT, Runx2, and β-catenin were measured. Compared with the control group, exogenous recombinant C3a and C5a treatment can promote the proliferation and early osteogenic differentiation of P-PDLSCs. Additionally, through KEGG enrichment, the Wnt/β-catenin pathway was identified as a key target. The pro-osteogenic effects of C3a/C5a were partially reversed by XAV939, pointing to a potential correlation with the Wnt/β-catenin signaling pathway. Exogenous recombinant C3a/C5a is associated with increased early osteogenic differentiation of P-PDLSCs, a process correlated with the activation of the Wnt/β-catenin signaling pathway, providing potential insights into regenerative strategies for periodontal tissues.
Adult hippocampal neurogenesis is altered after cerebral ischemia. Although stroke increases newborn neuron production, many cells display aberrant morphological and positional features that may impair functional integration and contribute to long-term cognitive deficits. Given the clinical heterogeneity of ischemic stroke and limited translational success of preclinical studies relying on single models, it remains unclear whether poststroke neurogenic alterations are conserved across experimental paradigms. This study aimed to identify common and model-specific features of hippocampal neurogenesis across focal ischemia models. We conducted a multicenter, multimodel analysis within the Stroke-IMPaCT consortium using permanent and transient middle cerebral artery occlusion paradigms, including distal middle cerebral artery occlusion under normoxic or hypoxic conditions (distal middle cerebral artery occlusion+hypoxia), and filament-based transient middle cerebral artery occlusion, across 6 sites. Adult C57BL/6J mice were analyzed at 3 days, 7 days, and 2 months after ischemia, sham, or naïve conditions. Hippocampal proliferation (Ki67) and neuroblasts (DCX [doublecortin]) were quantified; morphological maturation of newborn neurons was assessed through high-resolution analyses of dendritic architecture and somatodendritic polarity. Across all stroke models, ischemia induced a robust bilateral increase in hippocampal proliferation, most pronounced at 3 days and still elevated at 7 days, returning to baseline by 2 months. Neuroblast density was similarly increased at 7 days, particularly in the ipsilateral hippocampus, but normalized over time. Despite recovery in cell number, long-term analyses revealed a consistent reduction in apical dendrite length and increased proportion of neurons with aberrant features, including ectopic positioning, polarity defects, and abnormal lateral growth, across models and centers. Aberrant hippocampal neurogenesis represents a robust hallmark of poststroke pathology in mice, independent of ischemia type or surgical approach, despite known differences in the spatial distribution of primary injury across models. Our findings underscore the importance of considering structural quality, and not only quantity, of newborn neurons when evaluating poststroke plasticity and developing therapeutic strategies.
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Tumor-draining lymph nodes (DLNs) are crucial for the development of anti-tumor immunity upon irradiation. However, in radiotherapy, DLNs are frequently co-irradiated, which impairs their function. Here, we examine the consequences of DLN irradiation on anti-tumor immunity, focusing on the recently described radiotherapy-induced disruption of the CCR7-CCL19/CCL21 axis, which governs tumor-to-DLN trafficking. We use in vivo irradiated murine LNs and in vitro assays to assess irradiation-induced structural and functional changes in the DLNs. DLN-infiltrating lymphocytes and CCL19/CCL21 chemokines were depleted early after irradiation in a dose-dependent manner. Lymphocyte numbers recovered only in DLNs irradiated with 5 Gy or less. Lymphopenia persisted in DLNs irradiated with 15 Gy, with few surviving lymphocytes showing a compensatory increase in proliferation. Irradiation-deregulated secretion of CCL19 could be related to lymphodepletion and/or direct irradiation-induced processes in stromal cells. In conclusion, radiotherapy depletes DLNs, and impairs stromal function and chemokine signaling, thereby compromising anti-tumor immunity.
Multiple sclerosis (MS) is a chronic autoimmune disorder, in which the immune system targets the protective myelin sheath surrounding axons in the brain, spinal cord and optic nerve, leading to demyelination and ultimately neurodegeneration. Promoting remyelination to delay or halt disease progression remains a major therapeutic challenge in MS research. Matrix metalloproteases (MMPs) have been implicated in the pathogenesis of MS. Elevated levels of MMP-9 have been detected in cerebrospinal fluid (CSF), serum and demyelinating lesions of MS patients, where MMP-9 contributes to myelin breakdown, epitope generation, and leukocyte infiltration. In the in vivo experimental autoimmune encephalomyelitis and lysophosphatidylcholine (LPC) murine MS models, Mmp9-/- mice exhibited delayed resolution of disease symptoms, suggesting a role for MMP-9 in remyelination. In this study, we investigated the role of MMP-9 in demyelination and remyelination, using two complementary models: LPC-induced demyelination in ex vivo brain slices and cuprizone (CPZ)-induced demyelination in vivo. In LPC-treated slices, MMP-9 deficiency impaired remyelination via microglia/macrophage-mediated mechanisms. Consistently, Mmp9-/- mice displayed increased numbers of activated microglia/macrophages in the corpus callosum following CPZ intoxication, with modest persistence during remyelination compared to WT mice. Naïve Mmp9-/- microglia/macrophages also showed enhanced myelin debris phagocytosis compared to WT cells. However, MMP-9 deficiency had minimal impact on demyelination or remyelination in the CPZ model. Proteomic analysis of CSF revealed differential expression of inflammatory mediators, including decreased levels of CCL2 and CXCL9, whereas CCL20 was increased in Mmp9-/- CPZ-treated mice. Collectively, these findings indicate that MMP-9 does not directly regulate demyelination and remyelination in the CPZ-induced demyelination model, but increases microglial abundance, highlighting its indirect role in CNS demyelination.
Mucosal-Associated Invariant T (MAIT) cells are a subset of unconventional T cells that rapidly respond to early signs of inflammation, infection, and tissue damage. While MAIT cells have been typically associated with microbial infections, given their ability to respond to both microbial-derived riboflavin metabolites and proinflammatory cytokines such as IL-12, IL-15, or IL-18, their role in other inflammatory conditions remains mostly unknown. Alarmins, including IL-25, IL-33, and thymic stromal lymphopoietin (TSLP), are crucial effectors for early inflammatory responses, being released upon epithelial damage and strongly promoting the polarization of a wide variety of immune cells, including leukocytes like neutrophils, monocytes, macrophages, dendritic cells (DCs), NK cells, ILCs and T cells. However, how alarmins-induced environments influence MAIT cells' activity and function is yet to be explored. In this study, we investigate the roles of alarmins in controlling MAIT cell activation and function. We found that IL-33, but not IL-25 or TSLP, combined with the TCR-independent stimuli IL-12p70 (but not 5-OP-RU), induces a potent IFNγ secretory/cytotoxic program on MAIT cells. This response was strongly dependent on p38 MAPK signaling and glycolytic metabolism. Beyond IFNγ, IL-33/IL-12p70-activated MAIT cells secrete a diverse panel of immune mediators, including TNF, VEGF, OSM, CXCL11, and CCL3. Notably, conditioned media from purified Vα7.2+ T cells (enriched on MAIT cells) were able to polarize CD14+ monocytes towards a M1-like inflammatory phenotype, increasing both the expression of proinflammatory genes and phagocytic capacity. These findings reveal a broader immunomodulatory potential for MAIT cells to influence diverse immune compartments during inflammatory response.