International immunopharmacology最新文献

{"title":"Chronic psychological stress induces pulmonary dysfunction through alveolar macrophage-mediated activation of apoptotic signaling pathways","authors":"Lingmin Zeng ,&nbsp;Zihui Jin ,&nbsp;Yue Wang ,&nbsp;Xin Ning ,&nbsp;Zhou Yi ,&nbsp;Wangkai Chen ,&nbsp;Baichuan Wang ,&nbsp;Xinyu Li ,&nbsp;Tingting Zeng ,&nbsp;Jiaqi Zhao ,&nbsp;Cailian Fang ,&nbsp;Sitao Xie ,&nbsp;Lihong Li ,&nbsp;Run Xiao","doi":"10.1016/j.intimp.2026.116345","DOIUrl":"10.1016/j.intimp.2026.116345","url":null,"abstract":"<div><div>Anxiety and depressive disorders are frequently comorbid with respiratory diseases such as chronic obstructive pulmonary disease (COPD) and asthma. Yet the mechanisms linking these conditions remain poorly understood. Previous studies have focused on the regulatory role of stress response on neuroendocrine pathways, while the role of immune regulatory networks in this process remains elusive. Here, we established a chronic restraint stress (CRS) mouse model to investigate how chronic psychological stress affects pulmonary function by regulating the immune system. CRS markedly impaired lung function and induced emphysema-like pathological changes. Mechanistically, CRS induced excessive recruitment and activation of alveolar macrophages, which in turn triggered a cascade of apoptosis-related signaling events. Specifically, alveolar macrophages exhibited upregulated Fas ligand (FASL) expression, which promoted the Fas death receptor signaling pathway and activated downstream effector caspases (Caspase-3, Caspase-6 and Caspase-7). The activation of this pathway ultimately triggered extensive apoptosis of lung parenchymal cells, resulting in significant tissue damage. Moreover, depletion of alveolar macrophages significantly attenuated apoptosis in pulmonary parenchymal cells and restored lung function. Collectively, our study identifies an important regulatory axis linking chronic psychological stress to macrophage recruitment and pulmonary dysfunction. These findings provide a novel mechanistic framework for understanding the comorbidity between psychological stress and respiratory diseases.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116345"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dual-drug nanoplatform HPA@NPs reprograms the fibrotic microenvironment by suppressing EMT and M2 macrophage polarization in pulmonary fibrosis","authors":"An Chang ,&nbsp;Yi Wang ,&nbsp;Zan Cui ,&nbsp;Yuan-Yuan Liu ,&nbsp;Ling-Qi Meng ,&nbsp;Jia-Shi ,&nbsp;Zhi-Yong Qin ,&nbsp;Jia-Ning Gong","doi":"10.1016/j.intimp.2026.116362","DOIUrl":"10.1016/j.intimp.2026.116362","url":null,"abstract":"<div><div>Pulmonary fibrosis (PF) is a progressive and lethal interstitial lung disease, characterized by excessive extracellular matrix deposition and architectural distortion of the lung parenchyma. Its pathogenesis involves interconnected pathological events, including dysregulated epithelial-mesenchymal transition (EMT), chronic inflammation driven by M2-polarized macrophages, and abnormal fibroblast activation. These intertwined mechanisms contribute to the limited efficacy of current anti-fibrotic therapies, which often fail to achieve lesion-specific targeting and disease reversal. Moreover, the clinical utility of existing drugs is further hampered by poor bioavailability and insufficient accumulation at fibrotic sites. To overcome these challenges, we developed a multifunctional nanotherapeutic platform, termed HPA@NPs, through co-assembly of hyaluronic acid-platycodin D (HA-PD) and aspirin-platycodin D (ASA-PD) conjugates. This nanosystem enables concurrent modulation of multiple PF-relevant pathological features. Physicochemical characterization showed that HPA@NPs possess uniform nanoscale size, low critical aggregation concentration, and excellent colloidal stability, supporting prolonged blood circulation. In vitro, HPA@NPs showed efficient cellular uptake consistent with their HA-based design and were accompanied by inhibition of EMT, fibroblast activation, and M2 macrophage polarization, together with reduced expression of IL-10 and Arg-1. In bleomycin-induced PF mice, HPA@NPs significantly improved pulmonary function and attenuated histopathological damage. At the molecular level, HPA@NPs down-regulated fibrosis-related markers (Col1a1, TGF-β1, α-SMA), while up-regulating the epithelial tight-junction protein ZO-1 and down-regulating mesenchymal markers (N-cadherin, vimentin), confirming effective reversal of EMT. The therapeutic outcome of HPA@NPs surpassed that of monotherapy, highlighting a synergistic anti-fibrotic effect. Importantly, HPA@NPs exhibited no detectable cytotoxicity, hemolytic activity, or major organ toxicity at therapeutic doses, demonstrating favorable biocompatibility. In summary, HPA@NPs integrate precise targeting, multi-pathway synergy, and excellent biosafety, offering a promising translational strategy for PF treatment.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116362"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unraveling the matrix stiffness landscape in idiopathic pulmonary fibrosis: GSN and ARG1 as novel diagnostic biomarkers and potential therapeutic targets","authors":"Jian Chen ,&nbsp;Jingjing Meng ,&nbsp;Xiaolong Tang ,&nbsp;Guanchu Liu ,&nbsp;Keping Zhang","doi":"10.1016/j.intimp.2026.116334","DOIUrl":"10.1016/j.intimp.2026.116334","url":null,"abstract":"<div><h3>Background</h3><div>Idiopathic Pulmonary Fibrosis (IPF) is a progressive and fatal interstitial lung disease characterized by excessive extracellular matrix (ECM) deposition and tissue stiffening. Matrix stiffness is a key driver of fibrosis, yet diagnostic biomarkers directly linked to this physical property are lacking. This study aimed to identify robust matrix stiffness-related diagnostic biomarkers and potential therapeutic targets for IPF using an integrated machine learning approach.</div></div><div><h3>Methods</h3><div>Gene expression profiles were obtained from the GEO database (Training set: GSE33566; Validation set: GSE93606). Differentially expressed genes (DEGs) were intersected with a matrix stiffness-related gene set. Three machine learning algorithms (SVM-RFE, LASSO, and Naive Bayes) were employed to screen diagnostic feature genes. A diagnostic nomogram was constructed and evaluated. Functional enrichment (GO/KEGG/GSEA), immune infiltration (ssGSEA), and molecular docking analyses were performed to explore biological functions and predict therapeutic drugs.</div></div><div><h3>Results</h3><div>Eighteen matrix stiffness-related DEGs were identified. Through machine learning screening, GSN and ARG1 were determined as robust key genes, exhibiting high diagnostic accuracy (AUC &gt; 0.7) in both training and validation cohorts. Functional analysis revealed that GSN is involved in actin cytoskeleton regulation, while <em>ARG1</em> participates in immune response modulation. Both genes showed strong positive correlations with the infiltration of macrophages and neutrophils. Furthermore, molecular docking identified RA-2 as a potential therapeutic agent targeting <em>ARG1</em> with high binding affinity (−9.2 kcal/mol).</div></div><div><h3>Conclusion</h3><div>We identified <em>GSN</em> and <em>ARG1</em> as novel matrix stiffness-related diagnostic biomarkers for IPF, linking mechanotransduction to immune microenvironment remodeling. The diagnostic nomogram offers high clinical predictive value, and <em>RA-2</em> emerged as a putative ARG1-targeting compound with favorable docking energy and warrants further experimental validation as a potential antifibrotic agent.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116334"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lactate targeting: Regulatory networks and therapeutic potential in bone diseases","authors":"Xiyue Zhang ,&nbsp;Xiaoyuan Yan ,&nbsp;Wenqing Gao ,&nbsp;Jiawei Ma ,&nbsp;Zhuoyang Wu ,&nbsp;Na An ,&nbsp;Lihong Qiu ,&nbsp;Jiajie Guo","doi":"10.1016/j.intimp.2026.116376","DOIUrl":"10.1016/j.intimp.2026.116376","url":null,"abstract":"<div><div>Lactate, once regarded as a metabolic waste product, has emerged as a multifunctional regulator in skeletal pathophysiology. This review systematically elucidates the pivotal mechanisms underlying the role of lactate in bone-related pathologies, including inflammatory arthritis, osteoarthritis, osteoporosis, nonunion fractures, and primary bone tumors. Lactate functions through five integrated mechanisms: <em>i</em> serving as a rapid energy substrate; <em>ii</em> acting as an immunomodulatory mediator; <em>iii</em> enhancing osteoclast-mediated bone resorption through microenvironmental acidification; <em>iv</em> driving inflammatory cascades via G protein-coupled receptors (GPCRs); and <em>v</em> functioning as an epigenetic effector through histone and protein lactylation (Kla) to reprogram osteoblast and macrophage transcription. This review details the cell-specific effects of lactate on key bone-associated cells, including dynamic lactate-driven macrophage polarization, suppression or reprogramming of dendritic- and T-cell effector functions, glycolytic activation of fibroblast-like synoviocytes promoting joint inflammation, stimulation of osteoclastogenesis and bone resorption, and dose-dependent regulation of osteoblast differentiation and chondrocyte degradation. Therapeutic strategies targeting lactate metabolism, including lactate dehydrogenase A (LDHA) and pyruvate kinase M2 (PKM2) inhibitors, glycolysis modulators, monocarboxylate transporter (MCT) inhibitors, and potential interventions targeting “writers/readers/erasers” of lactylation, are evaluated. Finally, we propose future research directions regarding the role of lactate in bone diseases. This review highlights lactate as a strategic node that coordinates the bone immune–metabolic network, offering a promising target for the precise regulation of skeletal homeostasis and inflammation.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116376"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192728","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"An In Silico-Designed Chimeric Antigen Confers Broad Protection Against Major Diarrheal Pathogens (Shigella, ETEC, and EHEC) in Preclinical Models","authors":"Abbas Hajizade ,&nbsp;Ali Hatef Salmanian ,&nbsp;Firouz Ebrahimi ,&nbsp;Ayyoob Arpanaei ,&nbsp;Jafar Amani","doi":"10.1016/j.intimp.2026.116358","DOIUrl":"10.1016/j.intimp.2026.116358","url":null,"abstract":"<div><div>Diarrheagenic <em>E. coli</em> (DEC) and <em>Shigella</em> species are leading causes of under-5 mortality globally, prompting the development of a broad-spectrum vaccine. Here, we rationally designed a novel chimeric antigen (\"SEISL\") incorporating five virulence determinants: StxB and EspA (EHEC), LTB and a detoxified STa (ETEC), and the N-terminal domain of IpaD (<em>Shigella</em>). Bioinformatically optimized for maximal antigenicity, SEISL was expressed in <em>E. coli</em> BL21(DE3), purified from inclusion bodies under denaturing conditions, and confirmed by western blot. Immunization with SEISL + Freund’s adjuvants in pathogen-specific models elicited robust protection in all models.In rabbits (ETEC challenge), serum IgG significantly increased and ileal loop assays with virulent ETEC H10408 showed a significant reduction in fluid accumulation (p&lt;0.05). The Guinea pigs exhibited 71.4% protection against <em>Shigella flexneri</em>-induced keratoconjunctivitis in Sereny tests, and finally the mice (EHEC challenge) demonstrated elevated serum IgG and significant reduction in fecal shedding of EHEC O157:H7 post-challenge (p&lt;0.05). These results demonstrate that the SEISL antigen elicits broad protection immune responses against three critical diarrheal pathogens in preclinical models, providing proof-of-concept support for its continued development as a multipathogen vaccine candidate.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116358"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192738","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"miR-107-5p mitigates spinal cord injury by targeting the PLOD2/HK2 axis","authors":"Mengqiu Deng ,&nbsp;Guowei Jiang ,&nbsp;Kesheng Huang ,&nbsp;Shaowei Li ,&nbsp;Yun Xia ,&nbsp;Zhiwei Cao ,&nbsp;Wei Chen ,&nbsp;Ruifeng Ding","doi":"10.1016/j.intimp.2026.116355","DOIUrl":"10.1016/j.intimp.2026.116355","url":null,"abstract":"<div><h3>Background</h3><div>Spinal cord injury (SCI) induces persistent neuroinflammation and metabolic disturbances that contribute to neuropathic pain and neuronal damage. Although microRNAs are involved in these processes, their regulatory roles remain incompletely understood. This study aimed to identify miRNA-associated metabolic regulators linking glycolytic alterations with neuroinflammatory responses after SCI.</div></div><div><h3>Methods</h3><div>A contusion-induced mouse SCI model was used to assess behavioral sensitivity, motor function, and histological, molecular, and ultrastructural changes. Transcriptomic and microRNA profiling were performed to identify candidate regulators. Functional validation of miR-107-5p was conducted in BV-2 microglia and in vivo through overexpression studies, focusing on metabolic activity, microglial polarization, and cell death–related pathways.</div></div><div><h3>Results</h3><div>SCI reduced pain thresholds and motor performance and induced neuronal injury, mitochondrial abnormalities, and pro-inflammatory microglial activation. Transcriptomic analysis revealed sustained upregulation of the glycolytic regulators PLOD2 and HK2. Integrative profiling identified miR-107-5p as a potential upstream regulator of PLOD2. Overexpression of miR-107-5p in vitro and in vivo decreased PLOD2 and HK2 expression, reduced glycolytic activity, and attenuated inflammatory and apoptotic responses. These effects were diminished following PLOD2 knockdown, suggesting a PLOD2-dependent mechanism. Intrathecal administration of miR-107-5p in SCI mice was associated with higher pain thresholds, better motor performance, and reduced markers of neuroinflammation and neural injury.</div></div><div><h3>Conclusions</h3><div>miR-107-5p modulates glycolytic metabolism and inflammatory signaling after SCI, in part through regulation of the PLOD2/HK2 pathway. These findings provide mechanistic insight into miRNA-mediated metabolic regulation in SCI and support further investigation of miR-107-5p in the context of post-injury neuroinflammation.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116355"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179498","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thrombospondin-1-mediated macrophage efferocytosis dysfunction exacerbates intestinal pathology in Hirschsprung's disease","authors":"Qiuling Li ,&nbsp;Hanyi Kong ,&nbsp;Qijun Li ,&nbsp;Tingwei Chen ,&nbsp;Lei Chen ,&nbsp;Fan Wang ,&nbsp;Xinyu Zhang ,&nbsp;Yijun Wu ,&nbsp;Yu Zhu ,&nbsp;Zhi Geng ,&nbsp;Jiajia Zou ,&nbsp;Yan Chen ,&nbsp;Jun Liu ,&nbsp;Shungen Huang","doi":"10.1016/j.intimp.2026.116344","DOIUrl":"10.1016/j.intimp.2026.116344","url":null,"abstract":"<div><h3>Background</h3><div>Hirschsprung's disease (HSCR) is a prevalent pediatric congenital enteropathy characterized by disrupted intestinal homeostasis, persistent inflammation, and progressive intestinal fibrosis. However, the cellular and molecular mechanisms underpinning these pathological hallmarks remain incompletely elucidated. Given the pivotal role of macrophages in inflammation resolution and tissue repair, and the established function of thrombospondin-1 (THBS1) in regulating macrophage polarization and efferocytosis, we focused on THBS1 to dissect the mechanisms of HSCR-associated pathology.</div></div><div><h3>Methods</h3><div>Single-cell RNA sequencing (scRNA-seq) was performed on 3 paired colon biopsies of aganglionic HSCR lesions and proximal ganglionic controls. Inflammation and fibrosis markers were assessed in additional HSCR samples (<em>n</em> = 5) by histopathology, qRT-PCR, and immunofluorescence. Macrophage efferocytosis was quantified by flow cytometry and immunofluorescence. Mechanistic studies employed recombinant THBS1 (rTHBS1), siRNA/lentiviral transduction, CD36 inhibition, and Rac1 FRET biosensors in bone marrow-derived macrophages (BMDMs), with in vivo confirmation in DSS-induced colitis.</div></div><div><h3>Results</h3><div>scRNA-seq revealed stromal-specific THBS1 downregulation in HSCR as a top candidate regulator of dysregulated macrophage function. HSCR macrophages exhibited proinflammatory hyperactivation and impaired pro-resolving polarization with reduction of CD206⁺ proportion and downregulation of TGFB1. Mechanistically, THBS1 sustains intestinal homeostasis by mediating macrophage pro-resolving functions and enhances efferocytosis via activation of the CD36/Rac1 signaling axis. Inhibition of THBS1 abrogates macrophage efferocytosis by appropriate 50%, leading to unresolved inflammation and intestinal fibrosis. Critically, rTHBS1 treatment rescued efferocytosis in THBS1-deficient BMDMs. Notably, impaired macrophage THBS1 signaling was consistently observed in human HSCR specimens.</div></div><div><h3>Conclusion</h3><div>This study identifies stromal THBS1-CD36/Rac1 signaling as a critical regulator of macrophage efferocytosis and resolution in HSCR. THBS1 deficiency drives persistent post-surgical inflammation and fibrosis, establishing it as a novel therapeutic target and potential biomarker for precision interventions to improve long-term outcomes in this pediatric disorder.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116344"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146179491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginsenoside CK regulates non-alcoholic fatty liver disease by regulating liver fat metabolism and gut microbiota","authors":"Yifang Xiong ,&nbsp;Chenhui Zhu ,&nbsp;Yanru Chen ,&nbsp;Ru Xu ,&nbsp;Rongzhan Fu ,&nbsp;Xiaoxuan Ma ,&nbsp;Zhiguang Duan","doi":"10.1016/j.intimp.2026.116338","DOIUrl":"10.1016/j.intimp.2026.116338","url":null,"abstract":"<div><div>The global incidence of non-alcoholic fatty liver disease (NAFLD) is on a continuous rise, characterized by hepatic lipid metabolism disorder and gut microbiota dysbiosis. Although ginsenoside compound K (CK) exhibits hepatoprotective and anti-inflammatory activities, its specific role in the pathogenesis of NAFLD remains to be fully elucidated. In this study, a high-fat-high-cholesterol (HFHC) diet-induced NAFLD mouse model was used to investigate the protective effects of CK against the disease. The results demonstrated that CK intervention significantly attenuated HFHC diet-induced body weight gain in mice: the body weight of mice in the CK-L group (60 mg/kg) decreased by approximately 11.7%, hepatic inflammation was reduced by about 35%–45%, and lipid deposition was improved by roughly 50%–60%. Mechanistically, CK activates the peroxisome proliferator-activated receptor (PPAR) signaling pathway, regulates the expression of lipid metabolism-related genes and proteins, thereby ameliorating lipid metabolism disorder. Meanwhile, CK reverses HFHC diet-induced gut microbiota dysbiosis, upregulates the abundance of the beneficial bacterium Akkermansia, and modulates the intestinal phylum composition in NAFLD mice by increasing the proportion of Bacteroidetes and decreasing that of Firmicutes. CK regulates the occurrence and development of NAFLD via the gut-liver axis, providing experimental evidence for subsequent mechanistic research on NAFLD prevention and treatment as well as the exploration of candidate drugs.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116338"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Necroptosis mediated by FKBP5 in alveolar fibroblasts drives Pseudomonas aeruginosa-induced acute lung injury","authors":"Dong Zhang ,&nbsp;Yinghui Qu ,&nbsp;Yuexin Han ,&nbsp;Wei Liu ,&nbsp;Xiaozhi Wang ,&nbsp;Tao Wang ,&nbsp;Qian Qi","doi":"10.1016/j.intimp.2026.116368","DOIUrl":"10.1016/j.intimp.2026.116368","url":null,"abstract":"<div><div><em>Pseudomonas aeruginosa</em> (PA) is a leading cause of nosocomial infections and is frequently associated with severe dysregulation of the pulmonary inflammatory microenvironment. Alveolar fibroblasts can regulate the inflammatory microenvironment, but their specific role in PA-induced lung injury remains elusive. Using single-cell RNA sequencing, we identified a pro-inflammatory phenotype in fibroblasts during PA-induced acute lung injury, which was associated with high expression of the inflammatory target FK506 binding protein 51 (FKBP5). FKBP5 deficiency markedly alleviated inflammation and pulmonary edema in <em>Fkbp5</em>^−/− mice with bacterial lung injury. Consistently, single-cell RNA sequencing revealed that FKBP5 deficiency attenuated the pro-inflammatory phenotype of fibroblasts. Furthermore, alveolar fibroblast-specific conditional knockout of FKBP5 confirmed the critical contribution of FKBP5 in these cells to PA-induced inflammatory injury. Mechanistically, FKBP5 promoted necroptosis in alveolar fibroblasts, thereby activating NF-κB signaling, and driving neutrophil recruitment and activation, which collectively exacerbated lung injury. These findings identify FKBP5-mediated necroptosis in alveolar fibroblasts as a central mechanism of PA-associated acute lung injury and suggest FKBP5 as a promising therapeutic target.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116368"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146192735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Distinct roles of PINK1 autophosphorylation in neonatal hypoxia with or without convulsions","authors":"Yujie Zhai ,&nbsp;Xiaoqian Wang ,&nbsp;Hua Zhou,&nbsp;Yunrong Zhang,&nbsp;Qiaoyun Wang,&nbsp;Wenxiao Cao,&nbsp;Mengshuang Liu,&nbsp;Anqing Gao,&nbsp;Hongliu Sun","doi":"10.1016/j.intimp.2026.116343","DOIUrl":"10.1016/j.intimp.2026.116343","url":null,"abstract":"<div><div>This study explored the distinct roles of PINK1 in neonatal hypoxia with and without convulsions. Various models of hypoxia with different severities have been established using neonatal C57BL/6 J mice. In addition, short hairpin RNA (shRNA) interventions targeting translocase of the outer mitochondrial membrane 7 or mitochondrial ATPase associated with diverse cellular activities, such as protease 1 homolog, inhibitor, and promoter of PINK1 autophosphorylation, were administered to modulate PINK1 activity levels. After exposure to severe hypoxia (15 min) that induced convulsions, phosphorylated PINK1 levels increased, accompanied by enhanced mitophagy, increased mitochondrial reactive oxygen species, neuronal damage and elevated epileptic susceptibility. Moreover, inhibition of PINK1 phosphorylation alleviates oxidative stress injury and reduces epileptic susceptibility, whereas enhancement of PINK1 phosphorylation aggravates oxidative stress damage. PINK1-induced mitophagy and oxidative stress injury were also elevated following mild hypoxia (130 s), without convulsions. However, unlike the 15-min hypoxic condition, either increasing or suppressing PINK1 phosphorylation via shRNA intervention exacerbated hypoxia-induced injury. These findings suggest that excessive phosphorylated PINK1 levels following severe hypoxia with convulsions, promote neuronal injury and increase epileptic susceptibility. In contrast, moderate PINK1 phosphorylation, induced by mild hypoxia without convulsions, exerts neuroprotective effects. Overall, this study elucidates the dual roles of PINK1 autophosphorylation in neonatal hypoxia with and without convulsions, and provides a theoretical basis for the therapeutic modulation of PINK1 activity in neonatal hypoxia.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"174 ","pages":"Article 116343"},"PeriodicalIF":4.7,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146157087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}