Inflammation Research最新文献

{"title":"UBE2C-TRIM21-driven NOS2 degradation stabilizes Tregs and suppresses pyroptotic signaling in thyrocytes in Hashimoto's thyroiditis.","authors":"Xinyuan Cui, Yanting Mao, Bojin Xu, Mengru Yuan, Haiping Zhou, Shan Huang, Wenfang Peng","doi":"10.1007/s00011-026-02375-7","DOIUrl":"10.1007/s00011-026-02375-7","url":null,"abstract":"<p><strong>Background: </strong>Hashimoto's thyroiditis (HT) features persistent immune intolerance and progressive thyrocyte injury, yet the mechanistic linkage between regulatory T cell (Treg) instability and inflammasome-driven inflammatory damage in thyroid follicular cells remains unclear. We hypothesized that a Treg-intrinsic proteostasis module restrains inflammatory effectors to preserve immune tolerance and limit thyrocyte pyroptotic signaling.</p><p><strong>Methods: </strong>We integrated peripheral-blood Treg transcriptomics from HT patients and healthy controls with functional perturbation, proteomic interaction screening, ubiquitination reconstitution, immunometabolic profiling, and in vivo validation. Candidate regulators were prioritized using differential expression and network analyses, then interrogated in Tregs using gain/loss-of-function approaches and Transwell co-culture with primary thyroid cells. Protein-protein interactions were identified by Flag immunoprecipitation-mass spectrometry and validated by co-immunoprecipitation and BiFC. NOS2 ubiquitination and degradation were assessed by CHX chase, ubiquitination assays, linkage profiling, and in vitro reconstitution. Mitochondrial and metabolic consequences were evaluated by JC-1 staining and Seahorse OCR/ECAR assays. Translational relevance was tested in an experimental autoimmune thyroiditis (EAT) model with adoptive transfer of engineered Tregs and assessment of thyroid pathology, cytokines, autoantibodies, and pyroptosis-associated markers.</p><p><strong>Results: </strong>Ubiquitin-conjugating enzyme E2C (UBE2C) emerged as a consistently downregulated hub gene in HT-associated Tregs and was linked to ubiquitin-proteasome and inflammatory programs. UBE2C preserved the Treg suppressive program (FOXP3/CD25, IL-10/TGF-β), improved protection of thyroid cells, and reduced thyrocyte inflammasome/pyroptosis-associated signaling (NLRP3/ASC induction, caspase-1 processing, and GSDMD-N generation). TRIM21 was identified as a UBE2C-interacting E3 ligase partner that cooperated with UBE2C to drive predominantly K48-linked polyubiquitination and proteasomal degradation of NOS2 (with K516 as a key acceptor site). NOS2 accumulation impaired Treg mitochondrial membrane potential and shifted bioenergetics toward glycolysis, undermining Treg stability and restoring thyrocyte inflammasome activation. In EAT, adoptive transfer of UBE2C-enhanced Tregs mitigated thyroid inflammation, reduced TgAb/TPOAb, increased IL-10/TGF-β, and suppressed tissue pyroptosis-associated markers, whereas NOS2 reconstitution counteracted these benefits.</p><p><strong>Conclusions: </strong>The UBE2C-TRIM21-NOS2 axis defines a proteostasis checkpoint that stabilizes Tregs and disrupts a Treg-thyrocyte inflammasome-GSDMD injury loop, highlighting potentially actionable nodes for future tolerance-restoring strategies in HT.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149169841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammatory bowel disease and breast cancer: epidemiological evidence, shared biology, and clinical management.","authors":"Qianqian Han, Xiaoxiao Zhang, Sijie Li","doi":"10.1007/s00011-026-02390-8","DOIUrl":"10.1007/s00011-026-02390-8","url":null,"abstract":"<p><strong>Objective and design: </strong>This narrative review examines epidemiological, genetic, mechanistic, microbial, and therapeutic evidence concerning inflammatory bowel disease (IBD) and breast cancer.</p><p><strong>Methods: </strong>Relevant literature was identified through targeted PubMed searches completed through May 2026 and reference-list screening. Evidence was selected for its relevance to epidemiology, candidate mechanisms, microbiome-related pathways, and treatment interactions.</p><p><strong>Results: </strong>Pooled cohort evidence does not show a significant overall increase in breast cancer risk among patients with IBD. Several inflammatory, stromal, microbial, and endocrine pathways are relevant to both diseases, although most evidence comes from separate study populations and experimental models. Studies of patients with prior malignancy have not shown a clear increase in new or recurrent cancer during commonly used IBD therapies, but few analyses have focused specifically on breast cancer. Microbiome-directed treatments have been studied in IBD and, more recently, in oncology; their value for patients with both diseases is unknown.</p><p><strong>Conclusions: </strong>Current evidence does not support classifying IBD as a breast cancer risk state. The main clinical concern is the interaction between treatments for the two diseases, which requires individualized assessment and coordinated gastroenterology and oncology care.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149165965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamics and functional heterogeneity of FOXP3+ regulatory T cells in Trypanosoma cruzi infection: a systematic review.","authors":"Marcelo Eduardo Cardozo, Tatyane Martins Cirilo, Ana Laura Grossi de Oliveira, Ana Rafaela Antunes-Porto, Luisa Vitor do Braga Amaral, José Bryan da Rocha Rihs, Luisa Mourão Dias Magalhães, Lilian Lacerda Bueno, Fabiana Simão Machado, Ricardo Toshio Fujiwara","doi":"10.1007/s00011-026-02330-6","DOIUrl":"10.1007/s00011-026-02330-6","url":null,"abstract":"<p><strong>Background: </strong>The role of regulatory T cells (Tregs) in Trypanosoma cruzi infection remains unresolved, with conflicting evidence suggesting either protection from immunopathology or impairment of parasite control.</p><p><strong>Methods: </strong>We performed the first systematic review integrating data on Treg phenotype and function in human and experimental Chagas disease. A comprehensive search of PubMed, Embase, Scopus, and LILACS (2003-2025) identified studies assessing Tregs during T. cruzi infection. Study selection, data extraction, and risk-of-bias assessment followed PRISMA 2020 and Cochrane guidelines.</p><p><strong>Results: </strong>Twenty-seven studies met eligibility criteria (9 human, 18 murine). Human studies consistently showed that individuals with indeterminate Chagas disease harbor functionally stable Tregs enriched for CD39, CD25^high, and CTLA-4 expression. In contrast, Chagas cardiomyopathy was associated with Treg instability, PD-1 upregulation, and partial acquisition of Th1-like features. Murine models revealed a phase-dependent role: transient Treg restriction during acute infection enhanced CD8⁺ T cell-mediated parasite control, whereas failure to re-establish regulatory balance promoted chronic cardiac inflammation. Key modulatory pathways included IL-10, IL-2, IL-33/ST2, G-CSF, and CD39.</p><p><strong>Conclusion: </strong>These findings support a dual-role model in which Tregs dynamically coordinate disease tolerance. Treg-associated signatures, particularly CD39 expression and activated/resting Treg ratios, emerge as promising biomarkers and therapeutic targets for Chagas disease.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13658323/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149170021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epidermal retinoid starvation driven by AKR1B10 orchestrates barrier disruption and hyperinflammation in atopic dermatitis.","authors":"Fugang Xiao, Kerui Chen, Jialan Li, Lina Tan, Jinrong Zeng","doi":"10.1007/s00011-026-02388-2","DOIUrl":"10.1007/s00011-026-02388-2","url":null,"abstract":"<p><strong>Background: </strong>Atopic dermatitis (AD) is driven by a feed-forward loop of epidermal barrier disruption and immune dysregulation. Although retinoic acid (RA) signaling is indispensable for epidermal homeostasis and terminal differentiation, the molecular mechanisms underlying its functional exhaustion in eczematous lesions remain incompletely elucidated. To investigate whether the aldo-keto reductase AKR1B10 mediates intracellular RA depletion and epidermal dysfunction in AD, and to evaluate the therapeutic potential of topical aldo-keto reductase inhibition.</p><p><strong>Methods: </strong>We integrated single-cell RNA sequencing (scRNA-seq), bulk RNA-seq, and spatial transcriptomic datasets to identify AKR1B10 as a severity-associated metabolic candidate. In vitro, we performed siRNA-mediated knockdown and plasmid-based overexpression of AKR1B10 in HaCaT and primary human keratinocytes (NHEKs), complemented by RAR antagonist (AGN193109) blockade and exogenous atRA rescue. In vivo, we tested topical fidarestat in an MC903/OVA-induced AD mouse model.</p><p><strong>Results: </strong>AKR1B10 was significantly upregulated in AD keratinocytes, preferentially enriched in the stratum spinosum, and positively correlated with patient SCORAD scores (r = 0.70). AKR1B10 overexpression depleted intracellular atRA (validated by targeted LC-MS/MS), downregulated barrier proteins (FLG, KRT10, CLDN1), and induced pro-inflammatory mediators (IL-6, IL-8, CXCL1). AGN blockade abrogated the protective effects of AKR1B10 knockdown, while exogenous atRA rescued the overexpression phenotype. Topical fidarestat restored cutaneous atRA availability and RA target gene expression (CYP26A1, CRABP2), repaired epidermal architecture, and attenuated AD-like inflammation in vivo.</p><p><strong>Conclusion: </strong>AKR1B10 acts as a localized enzymatic sink that depletes intracellular RA pools, linking metabolic dysregulation to barrier disruption and hyperinflammation in AD. Topical aldo-keto reductase inhibition represents a promising, mechanistically grounded barrier-restorative strategy, although definitive AKR1B10-specific in vivo validation requires further study.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149167039","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell and spatial transcriptomics identify a JUNB+ neutrophil subset enriched in immune-excluded regions of lung adenocarcinoma.","authors":"Yaping Zhu, Danfei Shi, Longfei Ji, Binyu Wang, Weiyun Shen, Fengqi Liu, Siqi Zhang, Xinmin Li, Yong Li","doi":"10.1007/s00011-026-02377-5","DOIUrl":"10.1007/s00011-026-02377-5","url":null,"abstract":"<p><strong>Background: </strong>Tumor-associated neutrophils (TANs) display functional plasticity in lung adenocarcinoma (LUAD), but subsets linked to immune exclusion are poorly defined.</p><p><strong>Methods: </strong>We integrated single-cell RNA-seq, spatial transcriptomics, and bulk multi-omics data to characterize neutrophil heterogeneity in LUAD. Key findings were validated by immunofluorescence co-localization and qPCR on clinical blood and isolated neutrophils.</p><p><strong>Results: </strong>Neutrophils exhibited the highest scores for an EMT-associated transcriptional program and immune exclusion among all immune cell types. A distinct JUNB+ neutrophil subpopulation was spatially enriched in immune-excluded tumor regions and correlated with unfavorable prognosis. Spatial transcriptomic analysis revealed a significant positive correlation between JUNB expression and neutrophil marker module scores across tissue spots (Pearson r = 0.216 and 0.205, P = 1.84 × 10^-10 and 9.06 × 10^-11). Immunofluorescence confirmed JUNB protein co-localization with CD66b+ neutrophils in LUAD tissues (54.3% ± 8.2% of CD66b+ cells JUNB +). qPCR revealed specific upregulation of JUNB mRNA in circulating neutrophils from LUAD patients, whereas no difference was observed in whole blood.</p><p><strong>Conclusion: </strong>This study identifies JUNB as a marker of a neutrophil state associated with immune exclusion and poor prognosis in LUAD. The neutrophil-specific upregulation of JUNB highlights its potential as a circulating biomarker for TAN-mediated immunosuppression, which warrants validation in prospective cohorts.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109211","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dicer-independent miR-451a is upregulated in periodontitis and potentiates inflammation by impairing macrophage polarization and SOCS activity.","authors":"Raza Ali Naqvi, Jack Maddalozzo, Kreena Amin, Kristelle Capistrano, Araceli Valverde, Rani Rahat, Hasan Siddiqui, Wei Li, Christine D Wu, Shaoping Zhang, Mary Pettiette, Antonio Moretti, Gatikrushna Singh, Salvador Nares, Afsar Naqvi","doi":"10.1007/s00011-026-02381-9","DOIUrl":"10.1007/s00011-026-02381-9","url":null,"abstract":"<p><strong>Background: </strong>Periodontitis (PD) is characterized by localized inflammatory tissue destruction, yet the lesion-associated microRNA (miRNA)networks that regulate host immune responses remain incompletely defined. In this study, we aimed to identify and characterize dysregulated gingivalmiRNAs in PD that modulate inflammatory responses.</p><p><strong>Methods: </strong>Using a split-mouth design, miRNA expression was profiled in gingival biopsies fromperiodontal lesions and clinically healthy sites. Differentially expressed miRNAs were identified by microarray analysis, and selected candidates werevalidated by RT-qPCR. The responses of candidate miRNAs to periodontal bacterial challenge were evaluated, followed by functional studies ofmacrophage polarization, phagocytosis, inflammatory cytokine production, and target-gene regulation.</p><p><strong>Results: </strong>Microarray analysis identified 48differentially expressed miRNAs, including several upregulated non-canonical miRNAs. Among these, the Dicer-independent miRNAs miR-451a andmiR-1228 showed dose- and time-dependent induction following periodontal bacterial challenge. miR-451a, but not miR-1228, promoted a pro-inflammatory M1-like macrophage phenotype, characterized by increased HLA-DR and CD32 and reduced CD206 and CD163 expression. miR-451adirectly targeted multiple genes associated with M2 macrophage polarization, and its expression in inflamed gingival tissues inversely correlated with M2markers. miR-451a overexpression also reduced macrophage phagocytosis of E. coli and P. gingivalis while increasing pro-inflammatory cytokineproduction. Mechanistically, miR-451a directly suppressed SOCS3 and SOCS5, key negative regulators of JAK/STAT signaling, in TLR4-stimulated cells.The antagonistic expression patterns of miR-451a, SOCS3, and SOCS5 in PD further supported the functional relevance of this regulatory axis.</p><p><strong>Conclusion: </strong>miR-451a is a pathogen-responsive, PD-associated miRNA that promotes pro-inflammatory macrophage polarization, impairs bacterialphagocytosis, and amplifies inflammation through suppression of SOCS-mediated immune regulation. These findings identify the miR-451a-SOCS3/SOCS5 axis as a potential mechanism linking bacterial challenge to dysregulated macrophage responses in PD.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13642454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TMEM16F deficiency alleviates sepsis-induced acute lung injury through regulating macrophage polarization.","authors":"Meishan Yan, Caixu Liu, Xu Han, Siqi Li, Minghui Xu, Tingting Li, Li Chen, Qi Liu, Danfeng Hu, Zhihao Du, Gongchen Wang, Chunyan Gao","doi":"10.1007/s00011-026-02385-5","DOIUrl":"10.1007/s00011-026-02385-5","url":null,"abstract":"<p><strong>Background: </strong>Sepsis-induced acute lung injury (ALI) is closely associated with the balance of M1/M2 macrophage polarization and excessive inflammation. Recently studies have revealed that TMEM16F, a calcium-activated phospholipid scramblase, participates in modulating inflammatory response and oxidative stress. However, the effect of TMEM16F on regulation of M1/M2 polarization during sepsis-induced ALI and its underlying mechanisms remain unclear.</p><p><strong>Methods: </strong>In the present study, we utilized septic patients, lipopolysaccharide (LPS)-induced ALI mouse models, and LPS-treated mouse alveolar macrophages (AMs) as well as human THP-1-derived macrophages to investigate the potential functions and molecular mechanisms of TMEM16F in sepsis-induced ALI.</p><p><strong>Results: </strong>Our clinical analysis showed that TMEM16F mRNA levels in peripheral blood mononuclear cells (PBMCs) were positively correlated with inflammation and disease severity in septic patients. Additionally, TMEM16F was highly expressed in LPS-treated THP-1 macrophages and in vitro sepsis-induced ALI models. TMEM16F knockout significantly promoted M2 macrophage polarization, alleviated systemic inflammation, lung injury, oxidative stress and microthrombosis, and improved survival in septic mice. Mechanistically, TMEM16F could interact with SOCS3, suppressing downstream STAT3 signaling pathway and promoting NLRP3 inflammasome activation, resulting in increased M1 polarization and inflammatory response. Moreover, we identified platycodin D (PLD), a saponin found from Platycodon grandiflorum, could be an effective inhibitor of TMEM16F, and ameliorate sepsis-induced ALI by reprogramming macrophages towards an anti-inflammatory phenotype via inhibiting TMEM16F-mediated SOCS3/STAT3/NLRP3 pathway.</p><p><strong>Conclusions: </strong>Collectively, these findings indicated that TMEM16F plays a crucial role in regulating macrophage phenotypic switching, and highlighted targeting TMEM16F is a therapeutic strategy for attenuating sepsis-associated ALI through immune homeostasis restoration.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IL-18-associated basophil and mast cell activation in sepsis.","authors":"Junling Wang, Bingyu Qin, Xueyan Zhang, Mengmeng Zhan, Chao Chen, Junfen Li, Shihao Liu, Fangqiu Gu, Huanzhang Shao","doi":"10.1007/s00011-026-02386-4","DOIUrl":"10.1007/s00011-026-02386-4","url":null,"abstract":"<p><strong>Background: </strong>The contributions of basophils and mast cells to sepsis immunopathology remains poorly understood. Interleukin-18 (IL-18) has established roles in innate immune activation, but its relationships with basophil and mast cell activation during sepsis have not been fully defined.</p><p><strong>Methods: </strong>We investigated expression of IL-18Rα and activation marker CD63 on blood basophils of patients with sepsis using flow cytometry and RNA-sequencing. Sepsis mouse model and human cell lines were used to assess the effect of IL-18 on basophil and mast cell activation.</p><p><strong>Results: </strong>Close correlations between elevated plasma IL-18 level and increased CD63, IL-18Rα and IL-18Rβ protein expression on basophils of patients with sepsis were observed. Transcriptomic analysis revealed extensive reprogramming of septic basophils, including upregulation of CD63 and IL18RAP, together with enrichment of pathways related to ribosome biogenesis, mitochondrial translation, oxidative phosphorylation, proteasome, DNA replication and cell cycle. Furthermore, we observed increased expression of CD63 and IL-18Rα on basophils and mast cells in septic mice, and IL-18 upregulated their expression and mast cell accumulation in both healthy and septic mice. Additionally, elevated plasma and peritoneal levels of IL-18, IL-5, CCL2 and tryptase were observed in septic mice. In vitro experiments demonstrated that both IL-18 and plasma from patients with sepsis induced upregulation of CD63 and IL-18Rα on KU812 and HMC-1 cell lines.</p><p><strong>Conclusions: </strong>Collectively, our findings suggest that IL-18-associated basophil and mast cell activation may participate in sepsis-related inflammation.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-10-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149109095","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PP4 deficiency drives airway epithelial senescence via the PERK-eIF2α-ATF4-p21 axis in severe asthma.","authors":"Yu-Ting Huang, Chu-Yun Chen, Chih-Ming Weng, Shao-An Wang, Shih-Chang Hsu, Feng-Ming Yang","doi":"10.1007/s00011-026-02378-4","DOIUrl":"10.1007/s00011-026-02378-4","url":null,"abstract":"<p><strong>Background: </strong>Cellular senescence, defined by irreversible cell cycle arrest and the senescence-associated secretory phenotype (SASP), has emerged as a critical driver of airway inflammation and hyperresponsiveness in asthma. Despite well-established associations between senescence, aging, and chronic disease, its precise mechanistic role in asthma pathogenesis remains poorly understood. Protein phosphatase 4 (PP4), a serine/threonine phosphatase with broad physiological functions, is significantly downregulated in airway epithelial cells derived from patients with severe asthma, suggesting a potential regulatory role in disease progression.</p><p><strong>Method: </strong>Bulk RNA sequencing (RNA-seq) was performed to assess transcriptomic changes in PP4-deficient airway epithelial cells. Mechanistic studies examined downstream signaling through PERK phosphorylation, p21-dependent senescence pathways, mitochondrial function, and calcium dynamics. A house dust mite (HDM)-induced murine asthma model was employed to evaluate the therapeutic efficacy of the PERK inhibitor GSK2656157 in vivo. Ex vivo validation was conducted using air-liquid interface (ALI)-cultured human bronchial epithelial cells (HBECs) obtained from patients with severe asthma.</p><p><strong>Results: </strong>RNA-seq analysis revealed that PP4 deficiency significantly upregulates endoplasmic reticulum (ER) stress-related gene expression in airway epithelial cells. Mechanistically, PP4 loss enhanced PERK phosphorylation, activating the PERK-eIF2α-ATF4-p21 signaling axis, which in turn triggered p21-dependent cellular senescence, mitochondrial dysfunction, and intracellular calcium influx. In the HDM-induced asthma model, pharmacological inhibition of PERK with GSK2656157 attenuated airway epithelial senescence and significantly reduced systemic levels of IgE, IL-5, and IL-13. Consistently, GSK2656157 treatment effectively suppressed p21-mediated senescence and SASP in ALI-cultured HBECs from severe asthmatic donors.</p><p><strong>Conclusions: </strong>These findings demonstrate that PP4 governs airway epithelial senescence through the PERK-eIF2α-ATF4-p21 signaling axis, mechanistically linking ER stress to SASP-driven airway inflammation in asthma. Targeting PP4-related pathways represents a promising therapeutic strategy for managing senescence-associated pathology in severe asthma.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine learning-driven M2 macrophage signature for precision prediction of survival and therapy response in acute myeloid leukemia.","authors":"Fangmin Zhong, Jing Liu, Jingze Yue, Linlin Zhang, Guangyao Kong","doi":"10.1007/s00011-026-02379-3","DOIUrl":"10.1007/s00011-026-02379-3","url":null,"abstract":"<p><strong>Background: </strong>M2-type tumor-associated macrophages (TAMs) play critical roles in the immunosuppressive microenvironment and treatment resistance of acute myeloid leukemia (AML). However, their single-cell characteristics and predictive value for prognosis and therapy response remain unclear.</p><p><strong>Methods: </strong>Single-cell transcriptomic data from AML patients and healthy donors were integrated to characterize AML tumor-associated macrophages (AML-TAMs). CIBERSORT was used to evaluate M2 macrophage infiltration in the AML cohorts. WGCNA and machine learning were applied to construct an M2 macrophage-derived prognostic signature across 8 independent AML cohorts. The signature's predictive value for chemotherapy and immunotherapy response was assessed computationally, and further experimental validation was performed using clinical peripheral blood samples.</p><p><strong>Results: </strong>Single-cell analysis revealed a distinct AML-TAM subcluster with high CD163 expression enriched in immunosuppressive and stress-adapted pathways. M2 macrophage infiltration was greater in AML patients than in controls and was associated with shorter overall survival. High M2 infiltration correlated with adverse clinical features and was negatively correlated with CD8⁺ T cells. An 18-gene risk score model showed robust prognostic performance across eight cohorts (log-rank P < 0.001 for each). High-risk patients exhibited chemotherapy resistance, upregulated immune checkpoint genes, and a greater predicted response to anti-PD-1 therapy. Clinical validation confirmed increased M2 abundance and key gene expression changes in AML patients.</p><p><strong>Conclusions: </strong>This study characterizes M2 macrophages in AML at single-cell resolution and establishes an M2 macrophage-derived signature that enables robust prediction of survival and potential therapeutic response, providing a tool for risk stratification and personalized treatment.</p>","PeriodicalId":13550,"journal":{"name":"Inflammation Research","volume":"75 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2026-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149069185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}