Frontiers in Immunology最新文献

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron neurodegenerative disorder with a median survival of only 3-5 years. The heterogeneity of the disease and lack of effective therapies highlight the importance of identifying novel pathogenic mechanisms. We hypothesize that dysbiosis of gut microbiota enhances ALS by disrupting intestinal barrier function and altering metabolite profiles to drive systemic inflammation and neuronal stress. Precisely, the decrease in health-promoting bacteria (e.g., Akkermansia muciniphila, Bifidobacterium and Lactobacillus spp.) in ALS can reduce neuroprotective metabolite production (short-chain fatty acids, nicotinamide, GABA, precursors of serotonin) and increase gut permeability, enabling lipopolysaccharide (LPS) and pro-inflammatory cytokines into the circulation. Such changes would activate microglia and impair motor neuron homeostasis by glutamate excitotoxicity and mitochondrial dysfunction. The gut-brain axis operates through immune-mediated mechanisms, where ALS-associated microbiota changes compromise mucosal immunity and trigger peripheral Th1/Th17-biased responses with impaired Treg regulation. Elevated endotoxin levels correlate with TLR4-driven inflammation, promoting pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) that cross into the CNS and prime microglia toward a neurotoxic M1 phenotype, creating a milieu where IL-17A and other mediators directly injure motor neurons. Our hypothesis relies on establishing human and animal evidence of microbiome derangements, barrier dysfunction, and immune deregulation with ALS. We hypothesize that restoration of an "ALS-protective" microbiota consortium or its metabolic by-products can potentially slow disease progression. Testable hypotheses include improvement of ALS model motor deficits by probiotic or fecal-microbiota therapies, and normalization of inflammatory biomarkers. This paradigm recontextualizes ALS as a gut-brain disease and suggests new directions for translational research into this unmet medical indication.

Purpose: Depression is acknowledged to correlate with the occurrence and progression of multiple cancers. However, no study has yet systematically complied depression-related genes to construct a prognostic signature for lung adenocarcinoma (LUAD).

Methods: Our study encompasses 1,276 LUAD patients from three cohorts. Consensus clustering was employed to classify patients into different depression subtypes. Then, a variety of machine-learning algorithms were utilized to construct a robust depression-related signature (DRS). Thereafter, a nomogram combining DRS with common clinical characteristics was established for prognosis. The IOBR package was used to quantify the immune landscape, whereas the oncoPredict and Connectivity Map algorithms were employed to evaluate therapeutic response. The Seurat package was applied to process single-cell data, and the Scissor algorithm was used to identify depression-associated cells. Ultimately, depression-like mouse models were constructed to detect alternations in depression-related genes. In vitro experiments were performed to explore the role of PSEN1 in the malignant behaviors of LUAD.

Results: Unsupervised clustering stratified patients into two subtypes with distinct features. DRS consisting of 14 hub depression-related genes was established using the LASSO + GBM algorithm and served as an independent prognostic indicator. The nomogram constructed with DRS demonstrated robust predictive efficacy, with a C-index of 0.778. LUAD patients in the high-risk group exhibited weaker "immune hot" features and reduced responsiveness to immunotherapy. Additionally, high-risk patients were less sensitive to conventional chemotherapy and targeted therapies. Single-cell analysis revealed that depression-associated high-risk cells displayed more malignant characteristics. Finally, qRT-PCR validated the alternations of depression-related genes in depression-like mouse models, and in vitro experiments confirmed that PSEN1 facilitated cell proliferation in LUAD.

Conclusions: The molecular profile defined by the DRS can serve as an independent overall survival predictor and improve individualized treatment and clinical decision for LUAD patients. Of which, PSEN1 may contribute to depression-induced LUAD progression.

Background: Interstitial cystitis/bladder pain syndrome (IC/BPS), particularly the Hunner-type subtype (HIC), is a chronic inflammatory bladder disorder characterized by persistent inflammation and macrophage-driven immunometabolic dysregulation. CHI3L1, a secreted glycoprotein implicated in inflammation and tissue remodeling, is significantly upregulated in HIC and correlates with disease severity, but its mechanistic role in macrophage-mediated persistent inflammatory events (PIEs) remains poorly defined.

Methods: This study integrated multi-omics analyses, including bioinformatics of IC/BPS transcriptomic datasets, a cyclophosphamide-induced IC/BPS mouse model for in vivo validation, and in vitro functional assays involving CHI3L1 overexpression in macrophages. Transcriptomic, metabolomic, and molecular biology techniques were employed to evaluate metabolic shifts, inflammatory pathways, and transcription factor correlations.

Results: CHI3L1 expression was significantly upregulated in HIC patients, especially those with reduced bladder capacity, and correlated with inflammatory markers (IL-6, TNFα). In macrophages, CHI3L1 overexpression drove pro-inflammatory activation via NF-κB and TNF pathways, promoted glycolysis, and suppressed mitochondrial oxidative phosphorylation (OXPHOS) and aspartate metabolism. Critically, CHI3L1 expression strongly correlated with the transcription factor MYC rather than STAT3 under inflammatory conditions, reinforcing M1 polarization.

Conclusions: CHI3L1 exacerbates PIEs in HIC by reprogramming macrophage metabolism toward glycolysis and sustaining inflammation via MYC signaling. These findings establish CHI3L1 as a central regulator of chronic inflammation in HIC and highlight its potential as a therapeutic target for disrupting pathological immune-metabolic cycles.

Microsatellite-stable (MSS)/proficient mismatch-repair (pMMR) colorectal cancer (CRC) accounts for more than 85% of cases but responds poorly to single-agent immune checkpoint inhibitors (ICIs), with objective response rates remaining below 5%. A principal barrier to effective immunotherapy in these tumors is a durable immunosuppressive axis formed by myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) within the tumor microenvironment. This axis impedes antitumor immunity through multilayered mechanisms including bidirectional chemotactic recruitment, reciprocal cytokine signaling, metabolic suppression and exosome-mediated communication. CRC is uniquely influenced by the gut microbiota: Fusobacterium nucleatum promotes MDSC/Treg enrichment via TLR4-NF-κB and Fap2-TIGIT pathways; Peptostreptococcus anaerobius acts through integrin-PI3K-NF-κB signaling; and microbial metabolites such as 4-HPA activate JAK2/STAT3-CXCL3 signaling to expand MDSC populations. Concurrently, a hypoxia-lactate-HIF-1α-CD73/A2AR circuit further stabilizes suppressive phenotypes, forming a "microbiota-metabolism-hypoxia-MDSC-Treg" cascade. Emerging clinical and translational data indicate that disrupting this axis can sensitize MSS-CRC to ICIs: for example, Zanzalintinib combined with Atezolizumab reported survival benefit in the STELLAR-303 trial, and dual blockade of novel checkpoints with PD-(L)1 has been associated with enhanced immune activation in solid tumors. Targeting the MDSC-Treg axis therefore represents a promising strategy to overcome immunotherapy resistance in MSS/pMMR CRC.

Objective: Osteoarthritis (OA) involves an inflammatory imbalance, yet key mediators and their interplay with potential therapeutics like artemisinin (ART) remain poorly understood. This study aimed to systematically investigate these relationships using Mendelian randomization and to decipher their functional interactions through cellular and molecular experiments, complemented by network pharmacology and molecular docking analyses.

Methods: Using the Mendelian randomization (MR) method, we integrated independent exposure-outcome genome-wide association study data to evaluate the causal association between inflammatory cytokines and OA. Chondrocytes were treated with IL-1β, TGF-β1 (5 μg/mL), and ART (4 μg/mL) for 24 hours. Cell proliferation was assessed using CCK-8 and EdU assays, and gene/protein expression was analyzed via RT-qPCR, Western blotting, and immunofluorescence staining. In parallel, network pharmacology was performed to identify putative ART targets related to OA and to characterize enriched pathways and hub genes through GO/KEGG enrichment and protein-protein interaction (PPI) analyses. Molecular docking was further conducted to evaluate the binding feasibility between ART and the catabolic mediator MMP-13.

Results: MR revealed a positive association between TGF-β1 and OA risk (OR = 1.0526, P = 0.0182). Functionally, ART significantly enhanced chondrocyte proliferation, whereas TGF-β1 inhibited it. ART downregulated IL-1β and MMP13 expression, while TGF-β1 upregulated them, indicating opposing effects in OA chondrocytes. Network pharmacology suggested that ART-related OA targets were enriched in inflammation-associated processes and signaling pathways (e.g., MAPK signaling), with PPI analysis highlighting inflammatory signaling hubs (e.g., JAK/STAT-related nodes). Consistently, molecular docking demonstrated favorable binding of ART within the MMP-13 active pocket, supporting the structural feasibility of an ART-MMP-13 interaction.

Conclusion: This study demonstrates that TGF-β1 plays an important pathogenic role in OA, as supported by MR and in vitro evidence, while ART exhibits anti-inflammatory and anti-catabolic effects by counteracting TGF-β1-driven inflammatory responses. Network pharmacology and docking analyses further suggest multi-target pathway regulation and a potential interaction with MMP-13. ART may represent a viable therapeutic candidate for OA; however, further studies are required to validate direct targets and elucidate tissue-specific mechanisms.

Despite continuous exposure to dietary and microbial antigens, the intestinal mucosa maintains a delicate balance between immune activation and tolerance. This equilibrium depends on the integrity and regulatory functions of the intestinal epithelium and associated immune cells. In the case of celiac disease (CD), gluten ingestion disturbs this equilibrium in people with a genetic predisposition (those with HLA-DQ2 or HLA-DQ8 alleles), and this results in chronic inflammation and villous atrophy. Tissue transglutaminase 2 (TG2) modifies gluten peptides, thus enhancing their affinity for HLA-DQ2/8, with the downstream effect of triggering CD4⁺ T cell-mediated Th1 responses dominated by IFN-γ and IL-21. The same cytokines along with IL-15, which is released by the epithelial and dendritic cells, stimulate the activation of cytotoxic intraepithelial lymphocytes that, in turn, kill enterocytes. Additional innate pathways, including those induced by gliadin-derived peptides, α-amylase/trypsin inhibitors, and type I interferons, further amplify epithelial stress and immune activation. Crosstalk between immune and stromal cells and defects in counterregulatory mechanisms contribute to persistent tissue injury. Emerging evidence implicates the gut microbiota in modulating both gluten-dependent and -independent immune responses through protease activity and barrier regulation. We here review the available evidence supporting the role of immune cells in CD-associated tissue damage and discuss the basic mechanisms by which this destructive immune response is amplified.

Purpose: To investigate the inflammatory cytokine profiles in the aqueous humor (AH) of patients with Posner-Schlossman syndrome (PSS) and evaluate their correlations with key ophthalmic parameters.

Methods: Aqueous humor samples were collected from 31 eyes with PSS, 26 eyes with primary open-angle glaucoma (POAG), and 20 eyes with age-related cataract (ARC, control group) at the Eye and ENT Hospital of Fudan University. A multiplex bead-based flow cytometric immunoassay was performed to quantify the concentrations of interleukins (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-17), tumor necrosis factor-alpha (TNF-α), and interferons (IFN-α, IFN-γ). Simultaneously, the presence of cytomegalovirus (CMV) DNA in PSS samples was assessed by PCR. Clinical data including corneal endothelial cell density, visual acuity, intraocular pressure (IOP), and visual field were also recorded.

Results: The AH levels of IL-1β, IL-5, IL-6, IL-8, IL-10, IFN-γ, and TNF-α were significantly elevated in PSS patients compared to controls (P < 0.05), with IL-1β, IL-6, IL-10, and IFN-γ levels also significantly higher than in POAG patients. ROC curve analysis demonstrated diagnostic value of these four cytokines in differentiating PSS from POAG (P<0.05). No significant differences in cytokine levels were observed between CMV DNA-positive and -negative PSS samples. Notably, IL-6 levels positively correlated with IL-8 and IL-10, and also showed significant associations with IOP (r = 0.395, P = 0.007) and relative endothelial cell loss (RECL) (r = 0.453, P = 0.039).

Conclusion: Distinct inflammatory cytokine profiles in the AH of PSS patients suggest a prominent immune response potentially contributing to disease pathogenesis. IL-6 may serve as a biomarker reflecting both inflammation and tissue damage in PSS. Note: CECD, corneal endothelial cell density; RECL, relative decrease in CECD loss between the affected eye and the fellow eye.

Influenza A virus (IAV) infection activates multiple programmed cell death (PCD) pathways, which, while restricting viral replication and dissemination, concurrently disrupt the respiratory epithelial barrier and compromise immune homeostasis. Excessive activation of apoptosis, necroptosis, pyroptosis, and related processes results in tight junction(TJ) disruption, impaired mucociliary clearance and gas exchange, and amplification of inflammatory cascades, ultimately driving cytokine storm and severe tissue injury. This dual role of PCD underscores its importance in antiviral defense while exposing its potential to exacerbate immunopathology. Accordingly, this review focuses on IAV-induced PCD mechanisms, delineating their contribution to epithelial barrier breakdown and immune dysregulation, with the aim of informing strategies for precise modulation of immunopathological damage and improving therapeutic outcomes in severe influenza.

Purtscher-like retinopathy (PLR) is a secondary, non-traumatic occlusive microvascular retinal disease characterized by retinal leukoderma, hemorrhage, and cotton wool spots. It is commonly associated with conditions such as pancreatitis, renal disease, and infections including COVID-19 but is rarely reported in patients with hematologic malignancies, particularly following hematopoietic stem cell transplantation (HSCT). This article reports a case of relapsed B-cell acute lymphoblastic leukemia (B-ALL) in a patient who underwent multiple lines of immunotherapy, including CD19- and CD22-targeted CAR-T cells, inotuzumab ozogamicin (an anti-CD22 antibody-drug conjugate), and belimumab (a CD19/CD3 bispecific T-cell engager), followed by allogeneic HSCT from an unrelated donor. Early post-transplantation, an influenza A (H1N1) infection likely triggered the onset of PLR. On post-transplant day 160, the patient presented with sudden, painless vision loss in the left eye. Fundoscopic examination revealed retinal hemorrhages, Purtscher flecken, and macular edema, confirming the diagnosis of PLR. By day 194, new-onset thrombocytopenia, proteinuria, and progressively elevated serum creatinine levels suggested an association between PLR and transplant-associated thrombotic microangiopathy (TA-TMA). This case illustrates that multi-agent immunotherapy prior to HSCT for acute leukemia may cause cumulative endothelial injury and that influenza A infection can act as a trigger for PLR in the post-HSCT setting. Early recognition and management of PLR and TA-TMA could improve clinical outcomes. Consequently, close monitoring for these complications is essential in post-transplant patients, particularly those with a history of intensive immunotherapy or subsequent viral infection. Implementing a "systemic-local" endothelial monitoring framework may facilitate timely intervention and enhance patient prognosis.

Pregnancy requires major immunomodulatory changes, both systemically and locally, as the maternal immune system needs to be modulated to tolerate the semi-allogeneic foetus. Decidual macrophages and stromal cells, but also foetal tissues are involved in this immune tolerance, for example by inducing M2 macrophages and regulatory T cells. However, it is so far unknown whether foetal membrane cells such as amnion epithelial cells (AECs) can influence human macrophage polarisation. In this study, a human in vitro macrophage assay was employed to demonstrate that conditioned medium (CM) from AECs derived from term placentas induces M2 macrophage polarisation, and to compare AEC culture conditions aiming for efficient M2 polarisation. Macrophage colony-stimulating factor (M-CSF), a well-known M2-inducing cytokine, was found to be secreted by AECs, and M-CSF was partly responsible for the observed M2-polarising effect of AECs. In addition, the M2-polarising effect remained after removal of extracellular vesicles (EVs) from AEC-CM, suggesting the involvement of soluble but not of EV-associated mediators. Taken together, this study shows that AECs may contribute to the induction of the vital immunotolerant environment at the foetal-maternal interface. Based on their immunomodulatory effects observed here and in in vivo studies, AECs could be harnessed as cytotherapeutics for inflammatory disorders.