Inflammation Research[JOURNAL]
Sun
200 papers
IL-22/IL-22R signaling attenuates mitochondrial damage in PCOS by modulating granulosa cell lipid metabolism through ETS1.
Luo M, Chen Y, Chen H … +1 more , Wen Y
Inflamm Res · 2026 Mar · PMID 41842976 · Publisher ↗
OBJECTIVE: This study investigates the therapeutic potential of interleukin-22 (IL-22) in polycystic ovary syndrome (PCOS) and its mechanisms. METHODS: A dehydroepiandrosterone (DHEA)-induced PCOS mouse model and testost...
OBJECTIVE: This study investigates the therapeutic potential of interleukin-22 (IL-22) in polycystic ovary syndrome (PCOS) and its mechanisms. METHODS: A dehydroepiandrosterone (DHEA)-induced PCOS mouse model and testosterone-treated human KGN granulosa cells were utilized. Mice received IL-22 (50-100 µg/kg) or Diane-35 for 3 weeks. RESULTS: IL-22 administration restored estrous cyclicity, reduced ovarian cysts, and normalized serum testosterone and insulin levels in DHEA or letrozole-induced PCOS mice. DHEA induction led to mitochondrial damage in granulosa cells (GCs), evidenced by impaired mitochondrial membrane potential, mtDNA copy number depletion, and ROS accumulation, alongside lipid metabolic dysregulation. These detrimental effects were ameliorated by IL-22. Bioinformatics analysis of PCOS patient data revealed significant enrichment in lipid metabolism pathways. A high-fat diet abolished IL-22's PCOS-restoring effects, underscoring lipid metabolism as a key mechanism. We identified 19 lipid metabolism-related genes, with ETS1 being the most significantly regulated. IL-22 inhibited ETS1 expression induced by DHEA through the activation of STAT3 dependent on the IL-22R1, and Chromatin Immunoprecipitation (ChIP)-PCR confirmed STAT3 binding to the ETS1 promoter. CONCLUSION: Our findings highlight IL-22 as a promising therapeutic candidate for PCOS, acting through the IL-22R1/STAT3/ETS1 pathway to ameliorate mitochondrial dysfunction and lipid metabolic reprogramming in GCs. This study bridges immune signaling with metabolic pathology in PCOS, offering novel avenues for targeted intervention.
Immune checkpoint molecules beyond PD-1 and CTLA-4: emerging targets in autoimmune diseases and cancer immunotherapy.
Dadfar S, Eivazzadeh Y, Molavi H … +3 more , Abedi H, Tavassoli Razavi F, Haghmorad D
Inflamm Res · 2026 Mar · PMID 41842954 · Publisher ↗
BACKGROUND: Immune checkpoint molecules are pivotal regulators of immune activation and tolerance, playing critical roles in cancer, autoimmunity, infectious diseases, and transplantation. While programmed cell death pro...
BACKGROUND: Immune checkpoint molecules are pivotal regulators of immune activation and tolerance, playing critical roles in cancer, autoimmunity, infectious diseases, and transplantation. While programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) remain the most extensively studied checkpoints, immune checkpoint receptors beyond PD-1 and CTLA-4, including LAG-3, TIM-3, TIGIT, VISTA, BTLA, CD160, and CD96 have expanded our understanding of immune regulation. These pathways not only mediate immune evasion in tumors but also contribute to impaired tolerance in autoimmune diseases. KEY FINDINGS: Recent preclinical and clinical evidence highlights the potential of novel and next-generation checkpoint inhibitors (ICIs), either alone or in combination with established PD-1/CTLA-4 therapies, to overcome resistance in oncology. Concurrently, agonistic checkpoint modulation is being explored as a precision immunosuppressive strategy in autoimmune disorders, targeting dysregulated T-cell activation while preserving protective immunity. Key challenges remain, including heterogeneity in patient responses, immune-related adverse events (irAEs), and the need for robust biomarkers to guide personalized therapy. Advances in multi-omics profiling, artificial intelligence, and single-cell immune mapping promise to refine patient selection and optimize therapeutic regimens. Furthermore, the application of checkpoint modulation in chronic infections and transplantation underscores its broader potential beyond oncology. CONCLUSIONS: This review comprehensively discusses the mechanistic basis, therapeutic implications, combination strategies, and future directions of immune checkpoints beyond PD-1 and CTLA-4, emphasizing biomarker development, precision medicine approaches, and balancing efficacy with safety.
A 62-aa core of the cochlin LCCL domain induces macrophage M1 polarization in vitro.
Kim H, Bae SH, Jang SH … +6 more , Yoon S, Kim K, Jang SH, Gee HY, Kim Y, Jung J
Inflamm Res · 2026 Mar · PMID 41803274 · Publisher ↗
BACKGROUND: Cochlin, encoded by the COCH gene, mediates innate immunity against bacterial infections by segregating pathogens and recruiting immune cells through its N-terminal LCCL domain. This domain is cleaved and sec...
BACKGROUND: Cochlin, encoded by the COCH gene, mediates innate immunity against bacterial infections by segregating pathogens and recruiting immune cells through its N-terminal LCCL domain. This domain is cleaved and secreted to attract macrophages and neutrophils, but its core motif has remained unclear. METHODS: We designed and synthesized a shortened core peptide of the LCCL domain (cLCCL; 62 amino acids) preserving the conserved structural motif. Structural stability was predicted by in silico modeling. The immunomodulatory effects of LCCL and cLCCL were evaluated in RAW264.7 macrophage cells using bulk RNA sequencing, quantitative PCR, Western blotting, flow cytometry, and immunocytochemistry. RESULTS: RNA sequencing in RAW264.7 cells showed that both LCCL and synthetic cLCCL peptides induced M1 polarization, with upregulation of TICAM2, CD40, and CD86. Flow cytometry demonstrated a significant increase in CD40(+)/CD86(+) M1-polarized macrophages following LCCL or cLCCL treatment, with comparable effects between the full-length and core peptides. CONCLUSION: The identified cLCCL appears to promote pro-inflammatory macrophage polarization, activate pro-inflammatory innate immune pathways, and warrants further evaluation in mechanistic and in vivo studies.
Host immune dysfunction and Mycoplasma pneumoniae immune evasion: dual drivers of pathogenesis in Mycoplasma pneumoniae pneumonia.
Xiang H, Zheng C, Wang Y … +4 more , Sun Y, Li C, Cai M, Zhang Y
Inflamm Res · 2026 Mar · PMID 41774154 · Publisher ↗
Mycoplasma pneumoniae pneumonia (MPP) is a highly prevalent form of community-acquired pneumonia (CAP) that can be complicated by severe extrapulmonary manifestations, leading to poor prognosis. The immunopathogenesis of...
Mycoplasma pneumoniae pneumonia (MPP) is a highly prevalent form of community-acquired pneumonia (CAP) that can be complicated by severe extrapulmonary manifestations, leading to poor prognosis. The immunopathogenesis of MPP remains incompletely elucidated. This review synthesizes recent advancements, identifying host immune dysfunction and microbial immune evasion as the pivotal dual drivers of MPP immunopathogenesis. We detail how dysregulation of both innate and adaptive immunity—including impaired macrophage function, neutrophil-driven hyperinflammation, paradoxical natural killer (NK) cell activity, and imbalances in T-cell subsets—leads to ineffective pathogen clearance and promotes tissue damage. Concurrently, Mycoplasma pneumoniae perpetuates infection through strategies such as antigenic variation, the expression of an immunoglobulin-binding protein of Mycoplasma (IbpM), and intracellular invasion. Furthermore, we explore the role of autoimmune mechanisms, including molecular mimicry, in mediating extrapulmonary complications. Finally, we highlight the importance of translating these mechanistic insights into targeted immunotherapies and rational vaccine design, which are essential for overcoming current therapeutic limitations and improving clinical outcomes for patients with MPP.
Diagnostic significance of salivary and glandular siglec-5 in Sjögren disease and non-Sjögren sicca.
Castro FLAL, Nunes LFM, Felix FA … +13 more , Oliveira SR, de Arruda JAA, Drumond VZ, Abreu LG, Rocha ACH, Lara CM, Dos Santos HT, de Castro MAA, Ferreira GA, Tanure LA, Calderaro DC, Silva TA, de Sousa SF
Inflamm Res · 2026 Feb · PMID 41741798 · Full text
BACKGROUND: Sjögren disease (SjD) has a multifactorial pathogenesis that is not fully understood. Perceptions of disease severity shape healthcare-seeking behavior and engagement with diagnostic assessments, underscoring...
BACKGROUND: Sjögren disease (SjD) has a multifactorial pathogenesis that is not fully understood. Perceptions of disease severity shape healthcare-seeking behavior and engagement with diagnostic assessments, underscoring the need for objective biomarkers. Sialic acid-binding immunoglobulin-like lectins (siglecs) have emerged as relevant mediators in SjD immunopathology. PURPOSE: To investigate the diagnostic performance of siglec-5 expression in minor salivary gland (MSG) tissue and saliva samples from individuals with SjD and non-Sjögren sicca (nSS). METHODS: A total of 109 participants with SjD and 41 with nSS were included. Salivary concentrations of siglec-5/siglec-14, inflammatory markers (IL-6, IL-8, IFN-γ, IgA, IgG, nitric oxide [NO]), and neutrophil extracellular traps (NETs) were measured. Immunohistochemical analyses of siglec-5, CD20, and CD3 were performed on MSG specimens. The data were analyzed descriptively and analytically. RESULTS: Salivary levels of siglec-5/siglec-14, IgA, IgG, NO, and NETs were significantly higher in the SjD group compared to the nSS group. Elevated salivary levels of siglec-5/siglec-14, IL-6, and IgG were found among individuals with severe dryness scores. Immunohistochemical staining for siglec-5 was more pronounced in SjD samples and significantly associated with CD20 and CD3 positivity as well as the presence of xerophthalmia. Tissue infiltration by siglec-5 had greater diagnostic accuracy for SjD (area under the curve: 73.1% [95% confidence interval: 58.2–85]) than both salivary and ocular sicca tests. CONCLUSION: Siglec-5 expression was increased in individuals with SjD, supporting its involvement in disease pathogenesis as well as its potential usefulness as a biomarker. The availability of objective salivary and tissue markers may improve diagnostic pathways for SjD, thereby facilitating patient engagement.
Advances in the lectin pathway in systemic lupus erythematosus: from clinical correlations and mechanisms to targeted interventions.
Feng R, Zhang Y, Chen Q … +3 more , Wang Y, Tian Y, Xia Y
Inflamm Res · 2026 Feb · PMID 41741777 · Full text
BACKGROUND: The complement system critically mediates systemic lupus erythematosus (SLE) pathogenesis through dual mechanisms: promoting inflammatory organ damage while regulating the initiation of immune tolerance. Amon...
BACKGROUND: The complement system critically mediates systemic lupus erythematosus (SLE) pathogenesis through dual mechanisms: promoting inflammatory organ damage while regulating the initiation of immune tolerance. Among its three activation pathways (classical, alternative, and lectin), the lectin pathway is the most recently characterized. FINDINGS: The lectin pathway engages pattern-recognition molecules (PRMs: mannose-binding lectin [MBL], collectins, ficolins) and mannose-binding lectin-associated serine proteases (MASPs). These components orchestrate unique biological functions beyond canonical complement activation, including self-antigen clearance, B/T-cell tolerance modulation, and interferon-α production. PRM/MASP genetic variants (particularly loss-of-function genotypes) predispose to SLE and associate with organ-specific damage phenotypes. PRMs detect damage-associated molecular patterns on apoptotic cells, initiating complement activation. Resulting fragments (C3a, C5a) and membrane attack complexes directly drive tissue injury. Clinically, circulating PRM/MASP levels and tissue deposition patterns reflect disease activity and organ involvement. Although MASP-2- and C5-targeting monoclonal antibodies demonstrate therapeutic potential in trials, most lectin pathway interventions remain preclinical. CONCLUSIONS: This review integrates clinical correlations, mechanistic advances in both complement-dependent and complement-independent functions, and emerging SLE therapeutics targeting the lectin pathway.
FBXO6 mediated ubiquitination of SLC3A2 drives ferroptosis in ulcerative colitis: a machine learning and SHAP discovery.
Dai L, Yu C, Xu R … +5 more , Ge R, Zhang L, Li A, Xu X, Zhang Z
Inflamm Res · 2026 Feb · PMID 41741720 · Publisher ↗
BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease characterized by mucosal immune activation and epithelial barrier breakdown. The pathogenic mechanisms underlying UC remain incompletely understood, a...
BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory disease characterized by mucosal immune activation and epithelial barrier breakdown. The pathogenic mechanisms underlying UC remain incompletely understood, and identifying key molecular drivers of disease onset and progression may provide new therapeutic opportunities. METHODS: A total of 1,446 samples were integrated to identify key genes through machine learning and SHAP analysis. Immune infiltration, cytokine activity, barrier gene expression, and clinical outcomes were analyzed. Functional and mechanistic validations were further performed in lipopolysaccharide (LPS)-stimulated HT29 cells. RESULTS: FBXO6, COL1A2, and NPY emerged as robust diagnostic biomarkers that stratify UC patients into molecular subgroups with distinct inflammatory states and therapeutic responses. High FBXO6 expression correlated with macrophage-driven inflammation, barrier disruption, and reduced responsiveness to biologics. Mechanistically, FBXO6 directly bound SLC3A2 and induced its degradation through K48-linked ubiquitination, thereby promoting ferroptosis and amplifying mucosal inflammation. CONCLUSION: A previously unrecognized ubiquitin-mediated FBXO6-SLC3A2 axis was identified as a critical driver of ferroptosis and epithelial barrier disruption in UC. Targeting FBXO6 to preserve SLC3A2 stability is proposed as a potential therapeutic strategy to restore epithelial integrity and improve treatment responsiveness in patients with UC.
Thrombosis-related gene signature predicts prostate cancer recurrence and immune therapy: insights from retrospective cohorts, bioinformatics, and experimental validation.
Luo Y, Chen P, Situ M … +6 more , Zhuang W, Huang J, Wang B, Wang Q, Peng S, Huang H
Inflamm Res · 2026 Feb · PMID 41711904 · Publisher ↗
BACKGROUND: Thrombosis was recognized as a significant cause of morbidity and mortality for prostate cancer (PCa). The potential mechanisms underlying the effect of thrombosis on PCa remain elusive. METHODS: Retrospectiv...
BACKGROUND: Thrombosis was recognized as a significant cause of morbidity and mortality for prostate cancer (PCa). The potential mechanisms underlying the effect of thrombosis on PCa remain elusive. METHODS: Retrospective analysis of dual-center clinical data identified thrombosis-PCa correlations. Bioinformatics integration of TCGA-PRAD transcriptomics and thrombosis-related genes enabled construction of a prognostic signature, validated externally. Functional, immune, and drug sensitivity analyses were performed. Experimental validation included IHC, qPCR, IF, in vitro functional assays, and in vivo models. RESULTS: Elevated thrombosis risk strongly correlated with PCa aggressiveness and adverse clinical features. A five-gene risk model stratified PCa patients into distinct survival groups (low-risk: superior outcomes), validated by ROC/Cox analyses as an independent prognostic tool. Findings from functional enrichment, alongside evaluations of immune cell infiltration, immunotherapy responsiveness, and drug sensitivity, reinforced the capacity to accurately forecast the clinical efficacy of precision therapies, as validated by clinical relevance analysis and nomogram development. Immunohistochemistry and qPCR of signature genes revealed marked differences between PCa and adjacent tissues. Importantly, experimental knockdown of VAV2 in 22RV1 cells downregulated prothrombotic inflammatory factors (CXCL8, IL-6, and VEGF). Conditioned media from VAV2-knockdown cells markedly inhibited tube formation in HUVECs and suppressed NETs formation. In vivo, mice administered with conditioned media from VAV2-deficient cells exhibited prolonged PT and APTT, and reduced fibrinogen levels, indicating attenuated coagulation potential. CONCLUSION: We successfully developed and validated an innovative and robust five-gene signature, seamlessly integrating clinical prognostic parameters for the precise prediction of PCa patients outcomes. This dissertation offers an in-depth exploration of thrombosis, elucidating potential biological mechanisms underpinning therapeutic strategies related to tumor immunity in PCa.
Precision medicine in sepsis: reappraising glucocorticoid therapy through the lens of molecular endotypes.
Li J, Zhang Y, Jiang F … +4 more , Shi X, Tu M, Liu Z, Ye F
Inflamm Res · 2026 Feb · PMID 41703348 · Full text
Sepsis is a life-threatening organ dysfunction syndrome with high mortality. Due to the heterogeneity of its clinical manifestations and treatment responses, it has long faced great challenges in clinical management. In...
Sepsis is a life-threatening organ dysfunction syndrome with high mortality. Due to the heterogeneity of its clinical manifestations and treatment responses, it has long faced great challenges in clinical management. In recent years, the progress of molecular biology and omics technology has promoted the application of precision medical strategies based on molecular endotypes in sepsis research, which has opened up a new way for individualized treatment. Glucocorticoids are commonly used drugs in sepsis treatment, but their efficacy and safety vary significantly among patients with different molecular endotypes. The traditional one-size-fits-all therapy has been difficult to meet the complex clinical needs. This review systematically summarizes molecular endotype classifications in sepsis. It explores glucocorticoid mechanisms across different endotypes and summarizes recent clinical and preclinical advances. The article aims to provide theoretical foundations and practical guidance for precision therapy in sepsis, ultimately promoting personalized medicine in this field.
PINK1 deacetylation by emodin-induced SIRT3 upregulation alleviates acute kidney injury by Inhibition of ferroptosis.
Wang R, Zou Z, An Y … +4 more , Wang L, Li C, Zou Y, Wang G
Inflamm Res · 2026 Feb · PMID 41703345 · Publisher ↗
BACKGROUND: Acute kidney injury (AKI), characterized by rapid renal dysfunction and high mortality, is critically driven by ferroptosis, an iron-dependent form of cell death. While PTEN-induced kinase 1 (PINK1) and sirtu...
BACKGROUND: Acute kidney injury (AKI), characterized by rapid renal dysfunction and high mortality, is critically driven by ferroptosis, an iron-dependent form of cell death. While PTEN-induced kinase 1 (PINK1) and sirtuin 3 (SIRT3) are implicated in mitochondrial homeostasis and ferroptosis regulation, their mechanistic interplay in AKI remains unclear. This study investigated the role of emodin, a natural anthraquinone, in alleviating AKI via SIRT3-mediated PINK1 deacetylation and ferroptosis suppression, focusing on mitochondrial integrity, transferrin (TF) interaction, and redox balance. MATERIALS AND METHODS: Male C57BL/6 mice (n = 6/group), PINK1⁻/⁻, and SIRT3⁻/⁻ mice were pretreated with emodin (40-160 mg/kg, 3 days) before LPS-induced AKI (15 mg/kg). Human renal tubular HK-2 cells were treated with emodin (10-40 µg/ml) and Erastin (0.4 µM, 24 h). Assays included RNA sequencing, immunoprecipitation-mass spectrometry (IP-MS), histopathology (H&E/PAS/PB-DAB staining), ROS/Fe²⁺/GSH quantification, and immunoblotting. Statistical analysis used ANOVA and Student's t-test. RESULTS: Emodin reduced serum creatinine and urea in AKI mice, alongside decreased tubular injury and apoptosis. RNA-seq identified ferroptosis as the central pathway, with emodin upregulating PINK1 expression. IP-MS revealed emodin disrupted PINK1-TF binding via SIRT3-mediated deacetylation, reducing Fe²⁺ accumulation and restoring GPX4 levels. In SIRT3⁻/⁻ and PINK1⁻/⁻ models, emodin's protective effects were abolished, confirming pathway dependency. CONCLUSION: Emodin mitigates AKI by activating the SIRT3/PINK1 axis, suppressing ferroptosis through cytoplasmic PINK1 deacetylation and TF interaction disruption. These findings highlight SIRT3/PINK1 as a therapeutic target and emodin as a potential agent for AKI management.
Delayed disulfiram targeting GSDMD-NETs axis rescues sepsis by limiting bacterial spread and lung injury.
Shan X, Li Z, Dong L
Inflamm Res · 2026 Feb · PMID 41703331 · Publisher ↗
BACKGROUND: Sepsis therapy faces a critical paradox: Gasdermin D (GSDMD)-mediated neutrophil extracellular traps (NETs) exert protective host defense early but drive tissue injury late. Defining the temporal dynamics of...
BACKGROUND: Sepsis therapy faces a critical paradox: Gasdermin D (GSDMD)-mediated neutrophil extracellular traps (NETs) exert protective host defense early but drive tissue injury late. Defining the temporal dynamics of intervening in this axis is central to overcoming therapeutic limitations. METHODS: In a cecal ligation and puncture (CLP) model recapitulating human sepsis progression, disulfiram (DSF, 80 mg/kg) or vehicle was administered intraperitoneally at 0 h, 4 h, or 8 h postoperatively. A comprehensive multidimensional analysis assessed survival, bacterial burden (lung/blood/peritoneum), cytokines (TNF-α/IL-6/IL-1β), lung injury (histopathology/wet-dry ratio/Evans Blue extravasation), GSDMD activation, NET formation (Sytox-green/CitH3-MPO), and neutrophil function (LY6G infiltration/viability). RESULTS: Immediate DSF (0 h) proved detrimental, exacerbating bacterial dissemination (lung↑, P = 0.0036; blood↑, P = 0.0488), hyperinflammation (TNF-α↑, P = 0.0165; IL-6↑, P = 0.0140), and shortening survival (P = 0.0417). Conversely, delayed DSF (8 h) yielded significant benefits, reducing bacterial load (lung↓, P = 0.0002; blood↓, P = 0.0309), suppressing cytokines (TNF-α↓, P = 0.0121; IL-6↓, P = 0.0022), and extending survival (P < 0.0001). Mechanistically, while DSF consistently inhibited GSDMD cleavage and NETs, only delayed intervention attenuated NET-driven microthrombosis, reduced LY6G infiltration (P = 0.0112), and enhanced neutrophil viability (P = 0.0007). CONCLUSION: Targeting the GSDMD-NETs axis is fundamentally timing-dependent. Immediate inhibition disrupts essential host defenses, whereas delayed treatment (8 h post-CLP) preserves bacterial clearance, reduces lung injury, and improves survival. By establishing a therapeutic window, our study provides the first systematic evidence that the success of disulfiram in sepsis depends on when it is administered, offering a clinically actionable framework to guide future biomarker-driven trials and bedside decision-making in critical care.
Docosahexaenoic acid supplementation inhibits monocyte exhaustion memory formation during sepsis.
Caldwell BA, Wu Y, Ie S … +5 more , Lucas A, Conacher B, Zhang Y, Razani B, Li L
Inflamm Res · 2026 Feb · PMID 41703318 · Full text
OBJECTIVE AND DESIGN: Docosahexaenoic acid (DHA) is an omega-3 fatty acid with important roles in inflammation resolution. We tested the impact of DHA supplementation on monocyte exhaustion, an immune memory state contri...
OBJECTIVE AND DESIGN: Docosahexaenoic acid (DHA) is an omega-3 fatty acid with important roles in inflammation resolution. We tested the impact of DHA supplementation on monocyte exhaustion, an immune memory state contributing to chronic inflammation and immunosuppression following sepsis. MATERIALS OR SUBJECTS: Ex vivo sepsis modeling was performed with C57BL/6 mouse bone marrow monocytes (BMMCs) and peripheral blood mononuclear cells (PBMCs) from septic patients. TREATMENT: BMMCs stimulated with lipopolysaccharide (100 ng/mL) for 5 days were supplemented with 60 µM DHA. Septic patient PBMCs were treated for 24 h with 0, 15, 30, 45, or 60 µM DHA. METHODS: Monocyte exhaustion was assayed by flow cytometry, qRT-PCR, and cytometric arrays. DNA methylation changes linked to exhaustion memory were measured by bisulfite pyrosequencing. Western blots were performed to link DHA treatment to altered cell signaling pathways in septic monocytes. RESULTS: DHA supplementation suppresses the expression major exhaustion regulators CD38 and PD-L1 and dampens inflammatory cytokine transcription. These effects were mechanistically linked to STAT1/3 inhibition and accompanied by altered DNA methylation at immune regulators. DHA treatment also reduced CD157 cell surface levels and CCL2 secretion, both contributors to tissue invasion and injury during sepsis. CONCLUSIONS: Our results support the therapeutic application of DHA for the prevention of chronic immune dysfunction in sepsis survivors.
Heme oxygenase-1 emerges as a critical regulator linking autophagy dysregulation, immune infiltration, and NOD-Like receptor signaling in PCOS pathogenesis.
Wu X, Huang L, Guo S … +1 more , Zhou H
Inflamm Res · 2026 Feb · PMID 41703156 · Publisher ↗
BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder increasingly recognized to involve chronic inflammation, autophagy dysfunction, and immune imbalance. The molecular mechanisms connecting autop...
BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex endocrine disorder increasingly recognized to involve chronic inflammation, autophagy dysfunction, and immune imbalance. The molecular mechanisms connecting autophagy-related genes (ATGs), immune infiltration, and ovarian dysfunction remain unclear. METHODS: Transcriptomic data from ovarian granulosa cells (GSE34526 and GSE137684) were analyzed to identify differentially expressed ATGs, followed by functional enrichment, immune cell profiling, and network analysis. Ten hub genes were validated in clinical samples (PCOS and controls, n = 6 per group) and a dehydroepiandrosterone-induced mouse model. HMOX1 function was examined under conditions with and without metformin treatment. RESULTS: A total of 57 DEATGs were enriched in pathways related to autophagy, immune regulation, and inflammation, including the NOD-like receptor and FoxO signaling pathways. Among the ten identified hub genes, heme oxygenase-1 (HMOX1) was significantly upregulated in PCOS samples and positively associated with M2 macrophage infiltration. In vitro, HMOX1 overexpression led to increased levels of p62 and CD163, indicating impaired autophagic flux and enhanced M2-like polarization. Estradiol secretion was reduced under HMOX1 overexpression, and partially restored by metformin. In the PCOS mouse model, HMOX1 expression was elevated and suppressed following metformin treatment, although ovarian morphology remained abnormal. CONCLUSION: HMOX1 appears to act as a molecular nexus connecting impaired autophagy with immune microenvironment alterations in PCOS, highlighting its potential as both a diagnostic marker and a target for immunomodulatory therapy.
mTOR pathway mediates the endoplasmic reticulum stress -apoptosis of CD4+ T cell through inhibiting autophagy flux in sepsis.
Lei X, Zhao G, Xie Y … +1 more , Cui N
Inflamm Res · 2026 Feb · PMID 41653334 · Full text
BACKGROUND: CD4 + T cells are major reactive subpopulation for cellular and humoral immune responses following sepsis. The apoptosis of CD4 + T cells may contribute to sepsis-induced immunosuppression, and preventing the...
BACKGROUND: CD4 + T cells are major reactive subpopulation for cellular and humoral immune responses following sepsis. The apoptosis of CD4 + T cells may contribute to sepsis-induced immunosuppression, and preventing the induction of endoplasmic reticulum stress (ERS) can ameliorate apoptosis of CD4 + T cells in sepsis. The mechanistic target of rapamycin (mTOR) pathway performs an essential regulatory role on ERS-apoptosis of CD4 + T cells. This study aims to elucidate the underlying mechanisms of mTOR regulation of ERS-apoptosis of CD4 + T cells. METHODS: In this study, based on the cecal ligation and puncture (CLP) model, 4-phenylbutyric acid (4-PBA), we firstly detected the percentage of ERS-apoptosis of CD4 + T cells with flow cytometry, Western blotting. Next, we observed the autophagy process and related makers with transmission electron microscopy (TEM) and Western blotting. Furthermore, we created CLP models with T cell-specific mTOR and TSC1 genetic knockout mice, and bafilomycin A1(Baf-A1), a selective inhibitor of autophagy to explore the regulatory role and underlying mechanism of mTOR on ERS-apoptosis of CD4 + T cells. With rapamycin, we proved the clinical potential of mTOR. RESULTS: Here we observed a considerably higher percentage of apoptotic CD4 + T cells in sepsis, and 4-PBA (an inhibitor of ERS) could alleviate not only ERS, but also the apoptosis of CD4 + T cells. As our previous work proved, deletion of mTOR decreased ERS-apoptosis of CD4 + T cells in sepsis. Furthermore, deficient autophagy, especially impaired autophagic flux was observed in sepsis. Mechanistically, we found knockdown of mTOR erased impaired autophagic flux, decreased ER stress-induced apoptosis, which could be reversed by Baf-A1. More importantly, rapamycin (inhibitor of mTOR) showed great clinical potential. CONCLUSION: we proved that mTOR deletion could alleviate CD4 + T cells ERS-apoptosis by rescuing autophagy involving autophagosome -lysosome fusion. For the first time, we demonstrate the mTOR-autophagy-ERS-apoptosis axis in sepsis, enriching the targets for future discovery of new sepsis therapies.
Spatial transcriptomics identifies IL-32 as a lipid droplet-associated cytokine linked to tubular injury in human diabetic kidney disease.
Meadows K, Chung H, Vo S … +12 more , Imanzadeh A, Seo H, Belay SG, Swamy A, Teo W, Chapman K, Andonegui G, Benediktsson H, Stys PK, Pham T, Muruve DA, Chun J
Inflamm Res · 2026 Feb · PMID 41653322 · Full text
BACKGROUND: Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus and the leading cause of chronic kidney disease worldwide. Among the many drivers of tubular injury, lipid accumulation and inflamma...
BACKGROUND: Diabetic kidney disease (DKD) is a severe complication of diabetes mellitus and the leading cause of chronic kidney disease worldwide. Among the many drivers of tubular injury, lipid accumulation and inflammation are emerging as major contributors to kidney disease progression, but the molecular link between lipid metabolism and inflammatory signaling remains to be determined. METHODS: Kidney biopsies from patients with DKD across pathologic classes were labelled for lipid droplets and analyzed by Nile Red spectroscopy. Digital spatial profiling and single-cell spatial transcriptomics were performed on samples from 14 patients representing different DKD classes. RNA scope and immunofluorescence microscopy were used for data validation and characterization. RESULTS: Lipid droplets (LD) were increasingly abundant in advanced stages of DKD, primarily accumulating in the proximal tubules. Single-cell spatial transcriptomics identified several genes-DUSP5, AZU1, COL9A1, HSPB1, and IGFBP7-as highly upregulated in DKD. Remarkably, IL32, which encodes a LD-associated cytokine, was highly enriched in injured proximal tubules. Immunofluorescence confirmed IL-32 localization to LDs predominantly within KIM1 positive tubules in moderate to advanced DKD. Furthermore, injured IL-32 expressing tubules were in close proximity to infiltrating neutrophils and macrophages, immune effectors of non-resolving inflammation and kidney disease progression. CONCLUSION: IL-32 is a LD-associated cytokine upregulated during tubular injury that represents a potential link between lipid dysregulation, inflammation and progression in human DKD.
Role of neutrophils in regulating vascular permeability in inflammatory and autoimmune diseases.
Akbarzadeh R, Beerens M, Humrich JY … +4 more , Kusche K, Lamprecht P, Riemekasten G, Renné T
Inflamm Res · 2026 Feb · PMID 41653281 · Full text
BACKGROUND: Regulation of vascular endothelial permeability is crucial for maintaining hemostasis and controlling extravasation of immune cells in response to injury or infection. A transient increase in vascular permeab...
BACKGROUND: Regulation of vascular endothelial permeability is crucial for maintaining hemostasis and controlling extravasation of immune cells in response to injury or infection. A transient increase in vascular permeability is a vital response to inflammation, allowing neutrophils to invade the inflamed tissue and clear the pathogen. FINDINGS: The close interaction between neutrophils and the activated, inflamed endothelium, followed by leukocyte trafficking across the endothelial layer, can, however, also contribute to maladaptive vascular hyperpermeability. This increased permeability allows plasma proteins and fluid to escape into the surrounding tissue, leading to edema, a hallmark and frequent complication of many inflammatory disorders. Neutrophils also contribute to the resolution of inflammation by restricting further neutrophil recruitment through chemokine degradation, the formation of neutrophil extracellular traps (NETs), and by promoting their own apoptosis via the release of pro-apoptotic microparticles. Neutrophils, therefore, also contribute to the regulation of vascular permeability and to the restoration of tissue homeostasis in inflammatory conditions. IMPLICATIONS: This review summarizes the known mechanisms by which neutrophils regulate acute and chronic vascular permeability in autoimmune and non-autoimmune inflammatory diseases, and highlights the potential translational implications. Finally, we discuss overlapping and distinct mechanisms in neutrophil trafficking and vascular permeability.
Neutrophil extracellular traps induce airway epithelial-mesenchymal transition in a neutrophil-dominant asthmatic murine model through Hedgehog/Gli1 pathway.
Xia M, Wang Q, Jiang Y … +7 more , Lu S, Xu F, Yao Y, Li Y, Wu L, Zhou J, Zhou J
Inflamm Res · 2026 Feb · PMID 41622346 · Publisher ↗
BACKGROUND: Neutrophilic asthma is one of the main types of severe asthma. Our previous studies demonstrated that neutrophil extracellular traps (NETs) contribute to its pathological process. However, the underlying mech...
BACKGROUND: Neutrophilic asthma is one of the main types of severe asthma. Our previous studies demonstrated that neutrophil extracellular traps (NETs) contribute to its pathological process. However, the underlying mechanisms remains unclear. This study aimed to investigate the potential mechanisms of NETs in neutrophilic asthma. METHODS: Clinical samples were collected from patients with neutrophilic asthma and healthy controls. A neutrophil-dominant asthmatic murine model was established using ovalbumin (OVA), Freund's complete adjuvant (CFA) and lipopolysaccharide (LPS). Airway inflammation and remodeling were assessed by pathological staining. The expression of EMT markers and Hedgehog (Hh)/Gli1 pathway markers were measured by Western blot, qPCR, and immunofluorescence. RESULTS: We found that the expression of dsDNA, one of the skeleton components of NETs, was significantly higher in the peripheral plasma of patients with neutrophilic asthma than that of healthy controls, and neutrophils in neutrophilic asthma patients were more likely to induce the production of NETs. We further demonstrated that NETs induced EMT in airway epithelial cells. Both in vivo and in vitro, we confirmed that reducing NETs formation or enhancing NETs degradation reversed EMT process, attenuated airway hyperresponsiveness (AHR) and alleviated airway inflammation in neutrophil-dominant asthmatic mouse model. We also found that the Hh/Gli1 pathway was activated during this process, and inhibition of the Hh/Gli1 pathway also reversed the EMT process of airway epithelium. Similarly, AHR and airway inflammation in neutrophil-dominant asthmatic mice were reduced. CONCLUSIONS: We confirmed that NETs promote EMT in airway epithelium via activation the Hh/Gli1 signaling pathway, thus playing an important role in the pathogenesis of neutrophilic asthma. Targeting NETs or the Hh/Gli1 pathway may provide a promising therapeutic strategy for the treatment of severe neutrophilic asthma.
Immature leukocyte and plasma-induced cell death reveal subclinical immune activation in EGPA patients in remission.
Baggio C, Iorio L, Boscaro C … +10 more , Davanzo F, Davanzo V, Pelloso M, Tonello M, Sfriso P, Albiero M, Ramonda R, Doria A, Padoan R, Oliviero F
Inflamm Res · 2026 Feb · PMID 41622325 · Full text
OBJECTIVE: ANCA-associated vasculitis (AAV) is a group of rare autoimmune diseases characterized by pauci-immune necrotizing inflammation of small to medium-sized blood vessels, in which ANCAs targeting neutrophil antige...
OBJECTIVE: ANCA-associated vasculitis (AAV) is a group of rare autoimmune diseases characterized by pauci-immune necrotizing inflammation of small to medium-sized blood vessels, in which ANCAs targeting neutrophil antigens promote neutrophil activation, endothelial injury and organ damage. Although AAV follows a relapsing-remitting course, the immune landscape during remission remains poorly defined. This study investigated leukocyte alterations across AAV subtypes and examined whether plasma from ANCA-positive and ANCA-negative eosinophilic granulomatosis with polyangiitis (EGPA) patients in remission modulates peripheral blood mononuclear cell (PBMC) responses in healthy donors (HDs). METHODS: Peripheral blood was collected from 62 AAV patients in remission and 28 age- and sex-matched HDs. Leukocyte morphology was assessed via May-Grünwald Giemsa staining. Circulating cytokines and chemokines were quantified by ELISA. HD-derived PBMCs were exposed to plasma from EGPA patients, antiphospholipid-positive controls, or HDs. Cell death, metabolic activity, and cytokine production were evaluated using Trypan Blue, Annexin V/PI staining, MTT assays, and ELISA. Chemotaxis assays assessed cell migration in response to conditioned media, with or without Anakinra or CCR1 inhibitor J113863. RESULTS: AAV patients showed increased immature neutrophils. Plasma from ANCA-positive EGPA patients induced PBMC death, inflammasome-related cytokine release, and secretion of chemotactic and proangiogenic factors. Conditioned media enhanced immune cell migration in a cytokine-dependent manner. CONCLUSION: These findings indicate persistent subclinical immune activation during AAV remission, particularly in ANCA-positive EGPA, suggesting a role for mononuclear cell-mediated inflammation in relapse risk and the potential utility of immune monitoring.
Palmitic acid aggravates atopic dermatitis by regulating SGK1/NEDD4L-involved cutaneous neuroimmune inflammation through driving TRPV1 and MRGPRB2 S-palmitoylation.
Chen B, Yang J, Song T … +3 more , Wu W, Hao F, Yang Z
Inflamm Res · 2026 Feb · PMID 41622295 · Full text
OBJECTIVE: To determine how cutaneous palmitic acid (PA) modulates transient receptor potential vanilloid-1(TRPV1) in nociceptor and dorsal-root-ganglions (DRGs), and Mas-related G protein-coupled receptor B2 (MRGPRB2) i...
OBJECTIVE: To determine how cutaneous palmitic acid (PA) modulates transient receptor potential vanilloid-1(TRPV1) in nociceptor and dorsal-root-ganglions (DRGs), and Mas-related G protein-coupled receptor B2 (MRGPRB2) in mast cells (MCs), and to investigate their associations with serum- and glucocorticoid-regulated kinase-1 (SGK1)/neural precursor cell expressed developmentally down regulated 4-like (NEDD4L) in atopic dermatitis (AD). METHODS: AD was induced in mice with nedd4l or sgk1 conditional knock-out(cKO) in nociceptor, mrgprb2, nedd4l, or sgk1 cKO in MCs. Intradermal PA, substance P(SP), or pan-palmitoylation inhibitor 2BP was administered. Isolated DRGs and mouse bone-marrow-derived-MCs (mBMMCs) were used. RESULTS: Cutaneous PA levels were increased in AD mice.PA intradermal injection promoted a TRPV1 nociceptor-SP-MCs MRGPRB2-tryptase-AD axis. nedd4l cKO in nociceptor up-regulated cutaneous SP expression, which was further enhanced by PA. sgk1 cKO in nociceptor slightly reduced SP levels, which were further decreased by PA or 2BP. SP levels in mice with nedd4l or sgk1 cKO in MCs were increased by PA. In DRGs, supernatants from MC903-treated keratinocytes induced SGK1 and NEDD4L phosphorylation, TRPV1 S-palmitoylation, and SP production, all of which were up-regulated by PA; total and S-palmitoylated TRPV1 levels and SP production were increased following nedd4l knockdown, whereas they were slightly reduced following sgk1 knockdown and further decreased by PA. SP induced weak phosphorylation of SGK1 and NEDD4L in MCs. SP induced MRGPRB2 S-palmitoylation and tryptase release in wild-type, nedd4l or sgk1 knock-out MCs, and these effects were enhanced by PA; 2BP caused MRGPRB2 reduction in wild-type and sgk1 knock-out MCs. CONCLUSIONS: The increased cutaneous PA exacerbates AD by promoting TRPV1 S-palmitoylation and SP production in nociceptor, followed by MRGPRB2 S-palmitoylation and tryptase release in MCs. S-palmitoylation promotes TRPV1 whereas inhibits MRGPRB2 reduction via lysosome when NEDD4L and its upstream SGK1 are not phosphorylated.
Progressive resolution of reactive arthritis treated with Upadacitinib.
Zhang J, Zhang J, Yang F … +2 more , Li Q, Yin H
Inflamm Res · 2026 Feb · PMID 41622292 · Publisher ↗
Reactive arthritis (ReA) is a postinfectious inflammatory disorder that may be difficult to treat in refractory cases. We describe a 20-year-old man with HLA-B27-positive ReA presenting with arthritis, conjunctivitis, ba...
Reactive arthritis (ReA) is a postinfectious inflammatory disorder that may be difficult to treat in refractory cases. We describe a 20-year-old man with HLA-B27-positive ReA presenting with arthritis, conjunctivitis, balanitis, and psoriasiform skin lesions. Conventional therapies, including antibiotics, nonsteroidal anti-inflammatory drugs, corticosteroids, and sulfasalazine, failed to control disease activity. Treatment with upadacitinib (15 mg/day), a selective Janus kinase 1 inhibitor (JAK1), led to rapid improvement of joint, ocular, and cutaneous manifestations within three weeks. Corticosteroids were tapered and discontinued without relapse, and reduced-dose upadacitinib maintained remission for more than three months. This case highlights the potential role of JAK1 inhibition in ReA pathogenesis and suggests upadacitinib as a promising therapeutic option for refractory disease.
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