Podocyte injury and loss in diabetic nephropathy (DN) are driven by mitotic catastrophe (MC), a disastrous cell death caused by aberrant cell cycle re-entry. Ten-eleven translocation 2 (TET2), a 5-methylcytosine (m5C) RNA demethylase, was upregulated in DN and regulated cell proliferation. Here, we explored whether TET2 mediates podocyte MC in DN using Adriamycin (ADM) and high glucose (HG) in vitro, and both STZ-induced and db/db diabetic mouse models in vivo. TET2 was upregulated in human diseased kidneys and injured podocytes, and its expression correlated with disease severity and podocyte loss. EdU staining and flow cytometry verified that ADM/HG facilitated cell proliferation and G2/M phase transition via elevated CDK1-cyclin B1 phosphorylation; meanwhile, ADM/HG increased reactive oxygen species and malondialdehyde levels. TET2 overexpression further enhanced ADM/HG-induced podocyte MC and oxidative stress, whereas TET2 knockdown had the opposite effect. Mechanistically, TET2 reduced Wee1 mRNA stability in an m5C-dependent manner, leading to CDK1-cyclin B1 activation. Rescue experiments confirmed that Wee1 reintroduction rescued TET2-driven MC and oxidative stress, while Wee1 silencing abolished the protection from TET2 knockdown. In vivo, TET2 depletion or Wee1 overexpression alleviated podocyte MC, renal injury, and apoptotic podocytes in both diabetic models. Collectively, TET2 promotes podocyte MC and aggravates DN via TET2-mediated m5C demethylation that suppresses Wee1 expression and activates CDK1-cyclin B1, suggesting that this axis may represent a candidate pathway in the context of DN.
To investigate the role of the transcription factor FOXP1 and its target gene SDHAF2 in allergic rhinitis (AR), as well as their regulatory effects on ferroptosis in nasal epithelial cells. An AR mouse model and IL-4/IL-13-induced human nasal epithelial cells (HNEpCs) were used. Gene and protein expression, cytokine secretion, ferroptosis markers, nasal pathology, and AR symptoms were assessed via transcriptome sequencing, qRT-PCR, Western blot, ELISA, dual-luciferase reporter assay, co-immunoprecipitation, detection of Fe2+, ROS, GSH, MDA and lipid peroxides (LPO), and transmission electron microscopy. The biological functions of FOXP1 and SDHAF2 were explored through gene knockdown or overexpression, combined with the intervention of ferroptosis activator Erastin or inhibitor Ferrostatin-1. Sdhaf2 was significantly upregulated in AR models and closely associated with mitochondrial function and ferroptosis. Knockdown of SDHAF2 inhibited IL-4/IL-13-induced ferroptosis and inflammation in HNEpCs, whereas overexpression of SDHAF2 aggravated these phenotypes. The above changes could be modulated by Erastin or Ferrostatin-1. FOXP1 was highly expressed in AR models and transcriptionally regulated SDHAF2, which was verified by dual-luciferase reporter assays. SDHAF2 interacted with ALOX15 to increase ALOX15 expression and promote ferroptosis. Additional overexpression of ALOX15 reversed the inhibitory effect of SDHAF2 knockdown on ferroptosis. In OVA-induced AR mice, Sdhaf2 knockdown relieved nasal symptoms, reduced inflammatory cytokines, improved nasal pathological lesions and suppressed ferroptosis, and these protective effects were partially abolished by Erastin. FOXP1 upregulates SDHAF2. The encoded SDHAF2 protein interacts with ALOX15 to facilitate ferroptosis in nasal epithelial cells, thereby aggravating AR progression. The FOXP1/SDHAF2/ALOX15/ferroptosis axis may serve as a novel therapeutic target for AR.
Sepsis-induced cardiomyopathy is a serious complication of sepsis characterized by acute myocardial dysfunction and substantial mortality. This study evaluated the therapeutic effects of BGP-15 and the potential involvement of SIRT3/SOD2-associated signaling in a mouse model of cecal ligation and puncture (CLP)-induced sepsis. BGP-15 (20 or 40 mg/kg) was administered intravenously once at 6 h after CLP surgery. Survival, cardiac function, myocardial injury, oxidative stress, and inflammatory responses were evaluated. Myocardial SIRT3 expression, SOD2 Lys68 acetylation, and total SOD2 protein were assessed. The SIRT3 inhibitor 3-TYP was co-administered to investigate the potential involvement of SIRT3-related signaling in the effects of BGP-15. Sepsis was associated with cardiac dysfunction, increased mortality and myocardial injury, reduced myocardial SIRT3 expression, increased SOD2 Lys68 acetylation, and decreased total SOD2 protein. BGP-15 treatment improved survival and cardiac function, reduced serum CK-MB and LDH levels, and attenuated myocardial oxidative and inflammatory injury. High-dose BGP-15 increased SIRT3 expression, both BGP-15 doses reduced the Acetyl-SOD2/SOD2 ratio, and total SOD2 protein was increased. Co-administration of 3-TYP attenuated several cardiac, oxidative, and inflammatory effects associated with BGP-15 treatment, whereas its apparent attenuation of the 14-day survival benefit did not reach statistical significance (log-rank P = 0.1103). These findings support the involvement of SIRT3-related signaling in the cardioprotective effects associated with BGP-15 in experimental sepsis and support further preclinical investigation of BGP-15 for septic cardiomyopathy. SIRT3 and SOD2 enzymatic activities were not measured directly.
Microglial Toll-like receptor (TLR) 3 and 7 signalling is induced during active viral inflammation and emerging evidence suggests that it may persist in post-infectious state due to continued presence of free viral RNA. In addition, TLR3 and TLR7 can recognize self-derived RNA, leading to sustained microglial activation. TLR3 and TLR7 activation have also been implicated in neurodegenerative processes in major neurodegenerative disorders. However, the link between chronic TLR3- and TLR7-mediated neuroinflammation and progressive neuronal damage remains unclear. Neuronal-glial co-cultures and pure microglial cell cultures isolated from Wistar rat brain tissue were treated with synthetic TLR3 and TLR7 receptor activators—poly(I:C) and loxoribine. Neuronal density and viability were evaluated by double nuclear staining with Hoechst 33342 and propidium iodide. Microglial cell number and area were assessed by isolectin-IB4 labelling. Phosphatidylserine exposure on neuronal membranes was detected by Annexin V-Cy3 labelling. Evaluation of microglia activation (Iba-1 and CD68 expression), caspase-3 activation, synaptic density (synapsin-1/PSD-95 colocalization), neuronal (NeuN-positive cells) detection inside microglia were carried out by immunostaining. Levels of TNF-α, lactadherin and galectin-3 in cell culture medium were quantified by ELISA, while nitric oxide production was determined using Griess assay. Microglial phagocytic activity was assessed by measuring the uptake of phosphatidylserine-coated microparticles. In this study, we show that poly(I:C) and loxoribine induced loss of viable neurons without any increase in apoptosis (chromatin condensation/caspase-3 negative) or necrosis (propidium iodide negative) in neuronal-glial co-cultures. Neuronal loss was associated with alterations in microglial number and morphology, as well as enhanced production of pro-inflammatory factors and upregulated Iba-1 and CD68 expression. In co-cultures, poly(I:C) and loxoribine induced phosphatidylserine exposure on neuronal plasma membranes acting as ‘eat-me’ signal and opsonin lactadherin and galectin-3 production promoting phosphatidylserine recognition. NeuN-positive neurons exhibiting normal chromatin distribution were found inside of microglial cells, indicating their removal through phagocytic uptake. Under exposure to poly(I:C) and loxoribine, microglial cells showed enhanced phagocytic activity, evidenced by increased uptake of phosphatidylserine-covered polystyrene beads. Moreover, poly(I:C) and loxoribine were shown to induce microglia-dependent synaptic loss, indicating that TLR3 and TLR7 associated neuroinflammation contributes to both synaptic and neuronal pathology. Overall, our data suggest that synthetic TLR3 and TLR7 ligands poly(I:C) and loxoribine cause microglia-mediated neuronal and synaptic loss in neuronal-glial co-cultures through phagocytic uptake.
Small extracellular vesicles (sEVs) derived from tubular epithelial cells (TECs) are important mediators of tubular–immune cell communication in diabetic nephropathy (DN). However, the RNA cargo involved in TEC–macrophage inflammatory communication remains incompletely understood. This study investigated whether sEV-associated CCL5 mRNA contributes to inflammatory communication between TECs and macrophages in DN. Urinary sEV transcriptomic analysis and clinical association analysis were performed to identify DN-associated RNA cargo. In vitro, sEVs released from TECs exposed to high glucose were incubated with macrophages, and macrophage migration, inflammatory cytokine expression, and TLR4/MyD88/NF-κB-related signaling were evaluated. Ccl5 knockdown in TECs and actinomycin D experiments were used to examine sEV-associated Ccl5 mRNA enrichment, transfer, and function. CCL5 mRNA was increased in urinary sEVs in DN and was associated with tubulointerstitial injury in clinical samples. High-glucose-treated TECs released sEVs enriched in Ccl5 mRNA that were internalized by macrophages and enhanced macrophage migration, inflammatory cytokine expression, and TLR4/MyD88/NF-κB-related signaling. Ccl5 knockdown attenuated these effects, while actinomycin D experiments further supported the transfer of vesicle-associated Ccl5 mRNA. Activated macrophages also promoted injury-related responses in glomerular cells. These findings suggest that TEC-derived sEV-associated Ccl5 mRNA may contribute to TEC-to-macrophage inflammatory communication in DN, with activated macrophages potentially propagating injury-related responses to glomerular cells.
Juvenile dermatomyositis (JDM) is a rare systemic autoimmune disease primarily affecting children, with a female predominance. While muscle fiber inflammation has been extensively investigated, the contribution of the neuromuscular junction (NMJ) and its cellular microenvironment to JDM pathogenesis remains poorly understood. This study aimed to characterize NMJ-related gene expression patterns in JDM to identify potential pathogenic mechanisms and candidate biomarkers. An integrated transcriptomic analysis was conducted using two publicly available microarray datasets comprising 40 JDM patients and 22 healthy controls. Twenty-one genes representing five major NMJ functional categories were analyzed: cholinergic transmission, nicotinic acetylcholine receptors, extracellular matrix components, glial markers, and postsynaptic signaling molecules. Differential expression, discriminatory performance, correlation, clustering, and tissue deconvolution analyses were performed. Eighteen of the 21 NMJ-related genes were significantly differentially expressed in JDM (FDR-adjusted p < 0.05). Among these, MBP showed the most pronounced dysregulation and high discriminatory performance (AUC = 0.976, p = 6.10 × 10−16), with marked downregulation associated with increased muscle weakness. Other genes also demonstrated strong discriminatory performance, including AGRN (AUC = 0.941), NID1 (AUC = 0.932), CHRNA1 (AUC = 0.927), NRXN3 (AUC = 0.916), and RYR1 (AUC = 0.913). Correlation analyses revealed disruption of physiological co-expression patterns and the emergence of disease-specific interactions, including altered associations between glial markers and cholinergic components. CHRNA1 expression correlated with both muscle and skin disease activity scores, whereas GFAP expression was associated with disease duration. Clustering analysis indicated a reorganization of NMJ-related gene networks in JDM. Tissue deconvolution suggested that CHRNA1 expression may reflect a shift from inflammatory cell infiltration toward preservation of muscle cell identity. These findings reveal widespread NMJ-associated transcriptomic remodeling in JDM, involving synaptic, cholinergic, and neuroglial components. The identification of candidate transcriptional biomarkers, particularly MBP and CHRNA1, which show association with disease activity, may warrant further evaluation as potential monitoring tools in independent cohorts. Overall, this study supports a role for NMJ-associated transcriptomic remodeling in JDM pathophysiology and suggests new avenues for mechanistic investigation.
We developed ASTRA, a literature-informed, author-defined Astragalus mechanistic prior, and examined whether integrated and node-level whole-blood transcriptomic scores were associated with 28-day mortality in ICU sepsis. The primary analysis included 479 adults with sepsis from GSE65682; an exploratory cross-cohort directional assessment included 51 Day-1 patients with septic shock from GSE95233. Mean-Z scores were evaluated using age-adjusted logistic regression with false-discovery-rate correction. Sensitivity analyses included singscore, restricted cubic splines, label permutation, leave-one-gene-out analysis, correlations with IL1B and IL6 mRNA, and adjustment for transcriptome-derived myeloid-cell composition. The integrated ASTRA score showed a nominal inverse association with mortality but did not survive false-discovery-rate correction. The NLRP3-related three-gene score showed the strongest association in GSE65682 (OR per 1-SD increase, 0.70; 95
Observational studies on associations between various diseases and inflammatory bowel disease (IBD) are often limited by confounding and reverse causation. We aimed to assess potential causal relationships between a wide range of diseases and IBD, including Crohn’s disease (CD) and ulcerative colitis (UC). We performed a comprehensive bidirectional Mendelian randomization (MR) analysis of 104 common diseases and IBD traits using the generalized summary-data-based MR (GSMR) approach. Genome-wide association study (GWAS) summary statistics for diseases were obtained from the MRC Integrative Epidemiology Unit, and IBD data from the International IBD Genetics Consortium. Summary-data-based MR (SMR) integrating GWAS and expression quantitative trait locus data was applied to identify pleiotropic genes associated with IBD. MR analyses identified 38, 34, and 52 exposures significantly associated with IBD, UC, and CD, respectively. Childhood- and adult-onset asthma showed distinct causal effects on UC and CD. Reverse MR indicated associations between IBD traits and 15 diseases, including multiple sclerosis. SMR identified RGS14 and CARD9 as pleiotropic genes linked to IBD, suggesting shared genetic mechanisms with asthma and multiple sclerosis. These findings provide evidence for causal links and shared immune-related genetic mechanisms underlying IBD, highlighting potential targets for future research.
Activated macrophages release macrophage extracellular traps (METs), which are a major cause of tissue damage in sepsis. However, the molecular mechanisms governing their production remain poorly characterized. In this study, we demonstrate that MET levels are markedly elevated in both the liver and circulation in a lipopolysaccharide (LPS)-induced sepsis model. The immunometabolite itaconate—a product of the enzyme aconitate decarboxylase 1 (Acod1)—emerged as a critical suppressor of this pathway. Genetic ablation of immune responsive gene 1 (Irg1) resulted in heightened MET release, exacerbated hepatic injury, and decreased survival in septic mice. In contrast, the itaconate derivative 4-octyl itaconate (4-OI) robustly suppressed MET formation and ameliorated liver damage. Mechanistically, 4-OI activated the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2), resulting in scavenging of intracellular reactive oxygen species (ROS), which suppressed ROS-dependent activation of peptidylarginine deiminase 4 (PAD4), thereby inhibiting histone citrullination and subsequent MET release. The suppression of MET formation by 4-OI is mediated through an Nrf2-dependent mechanism, as its absence abolishes this suppression, revealing the Nrf2–ROS–PAD4 axis's key role. The findings reveal a new metabolic-immune pathway: itaconate reduces sepsis-linked liver injury by using Nrf2 to suppress METs, suggesting a novel clinical treatment approach.
Sarcopenia, characterized by the progressive loss of skeletal muscle mass and strength, is highly prevalent among cancer patients and is strongly associated with poor prognosis. Increasing evidence indicates that overactivation of the purinergic system contributes to a chronic inflammatory state that promotes tumor progression and exacerbates muscle wasting. This narrative review examines how physical exercise may modulate purinergic signaling and inflammation, potentially improving the quality of life of cancer patients with sarcopenia. A literature search was conducted in the MEDLINE database via PubMed, including articles published between 2008 and 2025, using descriptors such as “purinergic signaling”, “CD39”, “CD73”, “P2X7 receptor”, “adenosine”, “sarcopenia”, “skeletal muscle metabolism”, “cancer”, “inflammation”, and “extracellular ATP”. Original studies and review articles in English addressing the relationship between purinergic pathways, inflammation, muscle metabolism, and cancer were included. Findings suggest that cancer-related sarcopenia is closely linked to systemic inflammation mediated by purinergic pathways, and evidence indicates that exercise may play a pivotal role in mitigating muscle loss and improving patient outcomes.
Ulcerative colitis (UC) is a chronic inflammatory bowel disease driven by dysregulated immune responses, particularly the aberrant activation of T helper 17 (Th17) cells. While microbiome-based therapies show promise, wild-type probiotics often lack specific mechanisms to target the metabolic and immunological drivers of inflammation. In this study, we engineered a cysteine-auxotrophic strain of Bacteroides vulgatus (BV1608) by chromosomally integrating the E. coli cyuP gene to enhance cysteine uptake. We evaluated its colonization capability, safety, and therapeutic efficacy in dextran sulfate sodium (DSS)-induced acute and chronic colitis murine models. BV1608 exhibited superior colonization and cysteine assimilation compared to the wild-type strain. Oral administration of BV1608 significantly alleviated colitis symptoms, reduced pro-inflammatory cytokines, and restored intestinal barrier integrity. Mechanistically, BV1608 created a localized cysteine-restricted microenvironment in the gut and suppressed pathogenic Th17 differentiation. Under cystine-restricted conditions, ATF6 was activated in CD4⁺ T cells, and its inhibition partially restored IL-17A⁺ CD4⁺ T cell differentiation, indicating a functional role for ATF6. Meanwhile, cystine restriction was associated with increased BATF2 expression and enhanced ATF6 binding at the BATF2 promoter, suggesting BATF2 as a potential downstream node. Our findings demonstrate that metabolically engineered B. vulgatus BV1608 ameliorates colitis by coupling microbial cysteine sequestration with host immune modulation via the ATF6-dependent suppression of Th17 differentiation, while implicating BATF2-associated transcriptional regulation as a potential downstream mechanism. This study provides a novel synbiotic strategy for treating UC by targeting the immunometabolic interface.
This experimental study investigated theaflavin (TF) as a potential treatment for atherosclerosis (AS), focusing on its regulation of macrophage pyroptosis and autophagy via GSK-3β. Human aortic tissues from controls and subjects with AS, twelve male ApoE−/− mice, and ox-LDL-induced Ana-1 mouse macrophages, including Gsdmd/Caspase-1-overexpressing and Gsdmd-deficient cells, were studied. After 6 weeks of high-fat feeding, mice received TF (10 mg/kg/day, intraperitoneally) or PBS for 6 weeks; macrophages were stimulated with ox-LDL (20 μg/mL) and treated with TF for 48 h. Oil Red O staining, immunofluorescence, Western blotting, ELISA, CRISPR/Cas9, molecular docking, cellular thermal shift assay, and co-immunoprecipitation were performed. Data were expressed as mean ± SD and analyzed using unpaired two-tailed t-tests or ANOVA with Dunnett’s test. TF attenuated aortic plaque formation and reduced GSDMD-N, C-CASP1, NLRP3, and IL-1β. In vitro, TF suppressed lipid uptake in Gsdmd- or Caspase-1-overexpressing macrophages but showed no effect in Gsdmd-deficient cells. TF interacted with GSK-3β, reduced p-GSK-3β(Tyr216), promoted autophagy, and enhanced GSK-3β–cathepsin B interaction. TF attenuates AS progression by suppressing pyroptosis-mediated foam cell formation and promoting autophagy through modulation of GSK-3β activity.
Extrapulmonary tuberculosis (EPTB) represents a substantial proportion of tuberculosis cases, particularly among people living with HIV. Tuberculous lymphadenitis is one of the most common forms of EPTB and represents a condition in which the lymph node functions both as an immune-organizing site and a focus of Mycobacterium tuberculosis (Mtb) infection. Although peripheral blood biomarkers are frequently used to investigate immune responses in tuberculosis, they may not accurately reflect immunological processes occurring at the site of disease. In this study, we aimed to characterize and compare systemic and local inflammatory responses in individuals with suspected lymph node tuberculosis. We conducted a case–control study including 24 individuals undergoing lymph node biopsy for pathological lymphadenopathy at the National Institute of Infectious Diseases Evandro Chagas (Fiocruz), Brazil. Eleven participants were diagnosed with tuberculous lymphadenitis (45.8
Clear cell renal cell carcinoma (ccRCC) is the most common and aggressive form of renal malignancy. Although therapeutic strategies such as targeted agents and immune checkpoint inhibitors have progressed, the prognosis for patients with advanced ccRCC remains unsatisfactory. Cysteine-rich epidermal growth factor-like domain 2 (CRELD2), a protein localized to the endoplasmic reticulum, is involved in several biological processes, yet its function in ccRCC has not been clearly characterized. We conducted an integrative multi-omics study to investigate the role of CRELD2 in ccRCC. The study incorporated mendelian randomization (MR), bulk and single-cell RNA sequencing, immunohistochemistry, immune infiltration analysis, and spatial transcriptomics to explore expression patterns, prognostic value, cellular distribution, and potential biological implications of CRELD2. MR and summary-data-based MR analyses identified CRELD2 as a genetically supported candidate associated with RCC susceptibility. Elevated CRELD2 expression was confirmed at both mRNA and protein levels in ccRCC and correlated with worse overall survival independently. Single-cell analysis revealed preferential CRELD2 enrichment in endothelial and B-cell compartments, with CRELD2-high subsets showing shared enrichment of TNFA/NFκB, MTORC1, ROS, and oxidative phosphorylation pathways. Immune infiltration analysis linked CRELD2 expression to a B-cell-related immune infiltration profile, while spatial transcriptomics showed CRELD2 enrichment in tertiary lymphoid structure (TLS)-associated regions. Across single-cell and spatial analyses, TNFA/NFκB-related immune-inflammatory signaling represented a recurrent CRELD2-associated pathway feature. This study pointed out the CRELD2-centered TLS-associated immune-inflammatory conceptual axis, linking CRELD2 expression, endothelial/B-cell cellular contexts, B-cell-related immune infiltration, TLS-associated spatial localization, and recurrent TNFA/NFκB pathway enrichment via multi-omics and supporting it as a candidate therapeutic biomarker in ccRCC for further functional investigations.
This review summarizes the biological characteristics of mast cell-derived extracellular vesicles (EVs) and their roles in lung diseases involving mast cell activation and immune dysregulation, focusing on asthma, neonatal lung injury, and lung adenocarcinoma. Published studies involving mast cell lines, animal models, and patient-derived biospecimens on mast cell-derived EVs in pulmonary inflammation were summarized. Treatment: Not applicable. We synthesized evidence on EV biogenesis, cargo composition, target-cell interactions, immunomodulatory functions, and disease-specific roles. Mast cells are key effector cells in pulmonary inflammation whose functions extend beyond classical degranulation. They communicate with epithelial, stromal, and immune cells via EVs carrying proteins, lipids, mRNAs, and microRNAs. These vesicles modify recipient-cell function and mediate inflammatory amplification, epithelial injury, airway remodeling, and immune-cell activation. Mast cell-derived EVs exert disease- and context-dependent effects by regulating epithelial-immune crosstalk, type 2 inflammation, tissue remodeling, and tumor microenvironmental interactions. : Mast cell-derived EVs are key mediators of intercellular communication in pulmonary inflammation. However, most evidence comes from cell and animal models, and the clinical relevance of specific EV cargoes remains unclear. Further studies are needed to clarify their disease-specific mechanisms and evaluate their potential as biomarkers and therapeutic targets.
Sepsis remains a major cause of mortality, largely due to acute lung injury (ALI) driven by excessive neutrophil mediated inflammation. We recently identified a pathogenic subset of DLL4⁺ neutrophils that expands in inflamed lungs and promotes ALI, yet the underlying mechanisms remain unclear. Here, we investigated how DLL4⁺ neutrophils modulate alveolar macrophage (AM) function to exacerbate lung injury. AMs were treated with DLL4⁺ neutrophils or recombinant DLL4 (rmDLL4), and macrophage polarization was assessed by flow cytometry. Conditioned medium was subsequently applied to bone marrow-derived neutrophils (BMDNs) to evaluate neutrophil aging and CD47 expression (don't eat me signal on neutrophils). We showed that DLL4⁺ neutrophils activate the Notch1 signaling pathway in AMs, promoting toward a proinflammatory M1 phenotype. M1 cells markedly upregulate leukotriene B4 (LTB4) production through 5-lipoxygenase activation (5-LOX), inducing the accumulation of aged neutrophils (CXCR4hiCD62Llow). These aged neutrophils markedly increase CD47 expression, leading to impaired macrophage mediated phagocytosis and amplified lung inflammation. Importantly, we developed a novel DLL4-Notch1 inhibitory peptide (NDI) that reprograms AMs toward an anti-inflammatory M2 phenotype, reduces LTB4 release and aged neutrophils, lowers CD47 expression in a murine model of sepsis. Together, we identify DLL4⁺ neutrophils as key orchestrators of macrophage dysregulation in sepsis-induced ALI and demonstrate NDI may represent a potential therapeutic candidate in sepsis-induced ALI.
Lysophosphatidic acid (LPA) has been extensively reviewed in receptor pharmacology, fibrosis, cancer, vascular biology and neural injury. Its role in inflammation remains difficult to interpret because well-replicated pathogenic or pro-remodelling actions coexist with selected macrophage-regulatory effects reported under defined experimental conditions. This structured narrative review provides an evidence-weighted framework for interpreting these divergent findings. The strongest evidence supports LPA as an injury- and remodelling-associated signal in vascular–stromal programmes, pain-associated settings and tumour immune escape. By contrast, LPA-mediated attenuation of selected LPS/TLR4-driven macrophage responses is biologically plausible but incompletely replicated and receptor-divergent. The more specific LPAR1-dependent model of M2-like and metabolic macrophage reprogramming remains less independently validated, especially in primary human myeloid cells and physiologically plausible concentration ranges. LPA should not be classified as simply pro-inflammatory or anti-inflammatory. Anti-inflammatory LPA models should be regarded as experimentally plausible but translationally unproven until validated using defined LPA species, receptor-resolved perturbation and concentration-resolved human myeloid-cell systems.
Interferon-gamma (IFNγ) is a pivotal cytokine in immune surveillance and inflammation, yet its precise role in colorectal cancer (CRC) remains controversial due to its dual involvement in tumor suppression and immune evasion. Although natural killer cell receptor (NKR)+CD8+ T cells and invariant natural killer T (iNKT) cells contribute to anti-tumor immunity, how these cells regulate CRC progression under IFNγ-mediated, inflammatory conditions remains unclear. An azoxymethane/dextran sodium sulfate (AOM/DSS)-induced CRC model was established in heterozygous Yeti mice with IFNγ-mediated hyperinflammation. Using flow cytometry and histology, we evaluated tumor burden, histopathology, and immune cell infiltration in tumor tissues. NKR+CD8+ T cells were induced by IL15 treatment, and their anti-tumor efficacy was validated by adoptive transfer. The functional contribution of iNKT cells was assessed using iNKT cell-deficient Yeti/Jα18 knockout (KO) mice. Clinical relevance was determined by analyzing public transcriptomic datasets from non-metastatic and metastatic CRC patients using gene set enrichment (GSE) and protein interaction network (STRING) analyses. We found that Yeti mice display significantly blunted CRC development compared to wild-type (WT) controls. Furthermore, these IFNγ-mediated anti-tumor immune responses were attributed to increased tumor infiltration by CD8+ T cells expressing NKRs. Adoptive transfer experiments demonstrated that NKR⁺CD8⁺ T cells are potent anti-tumor effectors. Tumor-infiltrating iNKT cells in Yeti mice exhibited enhanced IFNγ and reduced IL10 production. Yeti mice lacking iNKT cells exhibited reduced tumor infiltration by NKR+CD8+ T cells, indicating that iNKT cells, particularly those producing IFNγ, are critical for controlling CRC development. Through GSE and STRING analyses, we found that non-metastatic patients exhibited increased IFNγ responses, reflected by greater enrichment of IFNγ-related gene ontology categories, compared with metastatic patients. NKR+CD8+ T cells in Yeti mice with elevated IFNγ levels suppress CRC development in an iNKT cell-dependent manner, suggesting that NKR+CD8+ T cells and iNKT cells cooperate to drive optimal anti-tumor immune responses against CRC during IFNγ hyperinflammation. Our findings highlight a potential immunotherapeutic strategy for CRC by reinforcing IFNγ-dependent anti-tumor responses.
Peripheral helper T cells represent a recently characterized subset of CD4+ T cells present in inflammatory bowel disease (IBD) patients. Bile acids act as signaling molecules in immune regulation. However, the role of bile acids in Tph cell differentiation remains unclear. Immunofluorescence staining was used to detect the presence of Tph cells in intestinal tissue samples; Wild-type (WT) and Fxr−/− mice were treated with or without the FXR agonist obeticholic acid (OCA) in dextran sulfate sodium (DSS)-induced acute colitis. The proportions of Tph cells and innate immune cells were analyzed by FACS. Bone marrow-derived dendritic cells (BMDCs) and naïve T cells of WT and Fxr−/− mice were sorted, differentiated and cultured in vitro to observe the regulatory effects of FXR on BMDCs function and Tph cell differentiation. Tph proportion was significantly elevated in inflamed intestinal tissues. OCA treatment increased the Tph cell proportion in the intestinal LP of WT mice. The proportion of dendritic cells (DCs) in the LP of Fxr−/− mice was significantly lower than WT mice after DSS-mediated colitis induction. FXR deficiency impaired the ability of BMDCs to induce Tph cell differentiation in vitro. CD11c and MHC-II expression levels were reduced in BMDCs from Fxr−/− mice upon stimulation with LPS. FXR deficiency activated the PPAR-γ signaling pathway and decreased IL-12 expression in BMDCs. Tph cell levels were elevated in inflamed intestinal tissues. FXR suppression in BMDCs was associated with activated PPAR-γ signaling; and with reduced DC maturation, IL-12 secretion, and Tph cell differentiation.
To identify shared molecular mechanisms and crosstalk genes (CGs) between diffuse large B-cell lymphoma (DLBCL) and primary Sjögren’s syndrome (PSS), and to explore the role of MICA in the immune microenvironment (IME). Bioinformatics analysis of GEO datasets identified differentially expressed genes (DEGs). Enrichment, immune infiltration, and Mendelian randomization analyses were performed. Diagnostic biomarkers were screened using Lasso regression. Functional roles of MICA were validated in SUDHL-6 cells via overexpression/knockdown, assessing immune cell infiltration, cytokine secretion, proliferation, and apoptosis. We identified 50 shared DEGs. RPL31, HNMT, and IFI27 were defined as diagnostic biomarkers. MR analysis confirmed a causal effect of PSS on DLBCL risk. MICA interacted with RPL31 and HNMT. MICA overexpression enhanced CD8+ T-cell infiltration and activation, elevated pro-inflammatory cytokine release, suppressed tumor cell proliferation, and promoted apoptosis. Conversely, MICA knockdown suppressed anti-tumor immune activity and promoted tumor growth. MICA plays a key role in shaping the immune microenvironment of DLBCL and PSS. By reinforcing anti-tumor immune responses and limiting tumor growth, it emerges as a promising biomarker and therapeutic target in both diseases.
