International immunopharmacology最新文献

{"title":"Neutrophil extracellular traps activate STING signaling to promote dendritic cell-driven rejection after liver transplantation","authors":"Yan Wang ,&nbsp;Jie Yin ,&nbsp;Chenjiang Yu ,&nbsp;Dongdong Wu ,&nbsp;Yizhang Chen ,&nbsp;Qi Han ,&nbsp;Shipeng Li ,&nbsp;Rui Zhang ,&nbsp;Wei Wang ,&nbsp;Jun Xu","doi":"10.1016/j.intimp.2025.114763","DOIUrl":"10.1016/j.intimp.2025.114763","url":null,"abstract":"<div><h3>Purpose:</h3><div>Post-transplant immune rejection affects graft function. Interaction between neutrophil extracellular traps (NETs) with specific immune cells and the specific mechanism in liver transplantation were still unclear.</div></div><div><h3>Method:</h3><div>Clinical patients RNA-Seq results were used for GSEA and KEGG analysis. C57BL/6 and C3H mouse models and clinical samples were use to describe the disease phenotype characteristics through multiple immunofluorescence, flow cytometry and etc. Cell co-culture experiments were performed to clarify the mechanism pathway process.</div></div><div><h3>Results:</h3><div>RNA-Seq results analysis indicated that the NETs formation pathway was upregulated. Animal models confirmed that in liver transplant immune rejection status the formation of NETs in situ and peripheral cells increased and the level of cell-free DNA (cf-DNA) in peripheral cells increased. Reactive oxygen species (ROS) as a predisposing factor for NETs accumulated more in immune rejection status and NETs are rich in mitochondrial DNA (mtDNA). NETs promote dendritic cell maturation through STING-related pathways. NETs formation increases in patients with liver transplant immune rejection and is positively correlated with disease severity.</div></div><div><h3>Conclusion:</h3><div>We found that NETs can regulate dendritic cell maturation through STING-related pathways after liver transplantation, which may ultimately promote the occurrence of liver transplant rejection, providing a new perspective for clinical diagnosis, treatment and prevention of liver transplant rejection.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114763"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170444","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":"CD34+CD45+ cells promote alveolar macrophage efferocytosis to alleviate phosgene-induced acute lung injury in rats","authors":"Xuanrong Bao ,&nbsp;Yu Dun ,&nbsp;Hanbing Hu ,&nbsp;Yuedong Tang ,&nbsp;Fuli Liu ,&nbsp;Jian Zhou ,&nbsp;Jie Shen","doi":"10.1016/j.intimp.2025.114968","DOIUrl":"10.1016/j.intimp.2025.114968","url":null,"abstract":"<div><div>Phosgene is still widely used in industrial production nowadays. However, as a toxic gas, accidental exposure to phosgene can lead to acute lung injury (ALI). Our team previously identified a cell subpopulation as CD34⁺CD45⁺ cells in the bronchoalveolar lavage fluid (BALF) of rats. CD34⁺CD45⁺ cells were demonstrated to possess stem cell properties and alleviate pulmonary inflammation during phosgene-induced acute lung injury (P-ALI). However, how CD34⁺CD45⁺ cells contribute to the anti-inflammatory process remains unexplored. Rats with P-ALI were intratracheally administered with CD34⁺CD45⁺ cells, and it was found that both the infiltration of macrophages and apoptotic cells were reduced in the lung tissues. The macrophages were polarized to an anti-inflammatory CD45⁺CD3⁻CD163⁺MHC-II^lo phenotype and restored efferocytosis efficiency, with a decreased level of inflammatory cytokines in the BALF. Moreover, it was observed that CD34⁺CD45⁺ cells promoted macrophage efferocytosis ex vivo and in vitro. Exosomes derived from CD34⁺CD45⁺ cells were further demonstrated to mediate the enhancement of macrophage efferocytosis. The small RNA sequencing analysis suggested that exosomal rno-miR-149-5p contributed to the effect. The transfection of rno-miR-149-5p mimic induced the enhancement of efferocytosis in macrophages as the exosomes did, while rno-miR-149-5p inhibitor attenuated the effect by exosomes. Our findings provide convincing evidence that CD34⁺CD45⁺ cells can alleviate ALI by enhancing macrophage efferocytosis, offering valuable insights into their therapeutic potential in managing chemical-induced acute lung injuries.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114968"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170551","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":"Astragaloside IV ameliorates Parkinson's disease by inhibiting TLR4/NF-κB-dependent neuroinflammation","authors":"Lixia Yang ,&nbsp;Haihua Huang ,&nbsp;Yue Fan ,&nbsp;Lei Xu ,&nbsp;Xiaoming Jin ,&nbsp;Baoguo Xiao ,&nbsp;Cungen MA ,&nbsp;Huijie Fan ,&nbsp;Zhi Chai","doi":"10.1016/j.intimp.2025.114972","DOIUrl":"10.1016/j.intimp.2025.114972","url":null,"abstract":"<div><div>Astragaloside IV (AS-IV) is a bioactive compound derived from <em>Radix Astragali</em>, a traditional Chinese herb widely used as a dietary supplement to enhance immune function. Modern pharmacological studies have demonstrated that AS-IV exhibits anti-inflammatory and immunomodulatory properties. In this study, we investigated the effects of AS-IV on motor dysfunction, microglial polarization, and immune regulation mechanisms in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) mouse model. Our results showed that AS-IV (40 mg/kg) significantly improved motor function in PD mice, as evidenced by reduced descent time in the pole test, increased hanging score in the hanging test, increased stride lengths, and reduced paw angle in the gait test. Furthermore, AS-IV administration attenuated the loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNpc), promoted microglial polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, suppressed the levels of pro-inflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNFα), enhanced the levels of anti-inflammatory cytokines including interleukin-4 (IL-4) and interleukin-10 (IL-10) in the SNpc of PD mice. Mechanistically, AS-IV significantly downregulated the expression and phosphorylation levels of TLR4/p38 (JNK)/NF-κB pathway-related proteins, including Toll-like receptor 4 (TLR4), Myeloid differentiation primary response protein 88 (MyD88), Apoptosis signal-regulating kinase 1 (ASK1), Mitogen-activated protein kinase 3/6 (MKK3/6), Phosphorylated-MKK3/6 (p-MKK3/6), Phosphorylated-mitogen-activated protein kinase 4/7 (p-MKK4/7), p38 mitogen-activated protein kinase (p38), Phosphorylated-p38 (p-p38), c-Jun N-terminal kinase (JNK), Phosphorylated-JNK (p-JNK), nuclear factor kappa-B (NF-κB), and Phosphorylated-NF-κB (p-NF-κB). To further validate the targeting effect of AS-IV, 1 mg/kg of LPS-EB Ultrapure was utilized as a specific TLR4 agonistwe to selectively activated the TLR4/NF-κB signaling pathway without triggering other inflammatory pathways, leading to elevated mRNA levels of TLR4, NF-κB, IL-1β, IL-6, TNFα and protein expression of TLR4, p-JNK, p-p38, p-NF-κB, IL-1β, IL-6, TNFα in the SNpc of PD mice. Importantly, AS-IV pretreatment can't counteract these LPS-EB Ultrapure-triggered effects, demonstrating its dependence on the TLR4/NF-κB signaling pathway. In conclusion, our findings indicate that AS-IV modulates microglial polarization and attenuates neuroinflammation by inhibiting the TLR4/NF-κB pathway, thereby ameliorating motor dysfunction and neuronal loss in PD mice.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114972"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170548","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":"Mitophagy-mtROS axis contributes to anti-tuberculosis-induced liver injury through activation of the cGAS-STING pathway in rat hepatocytes","authors":"Wenyan Chen ,&nbsp;Chenjunlei Luo ,&nbsp;He Zhou ,&nbsp;Zhenhui Liu ,&nbsp;Junfei Huang ,&nbsp;Yining Liu ,&nbsp;Mingdan You ,&nbsp;Guanghong Yang","doi":"10.1016/j.intimp.2025.114984","DOIUrl":"10.1016/j.intimp.2025.114984","url":null,"abstract":"<div><div>Tuberculosis (TB) remains a major worldwide healthcare issue, with anti-TB drugs playing a pivotal role in its treatment. However, the emergence of anti-TB drug-induced liver injury (ATB-DILI) poses a considerable challenge, undermining treatment efficacy and patient survival. This study investigates the underlying mechanisms of ATB-DILI, focusing on reactive oxygen species (ROS), mitophagy, lysosomal function, and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway. A rat hepatocyte model treated with standard anti-TB drugs was established to assess liver inflammation, oxidative stress biomarkers, mitochondrial function, and mitophagy processes. The results indicate that anti-TB drug administration induced significant inflammatory injury, characterized by elevated IL-6 and reduced IL-4 and IL-10 levels. ROS overproduction predominantly originates in the mitochondrial level, consequently resulting in oxidative stress and impaired mitochondrial function. A noticeable decline in both the oxygen consumption rate and ATP production is indicative of this phenomenon. Although mitophagy was activated, impaired lysosomal function hindered mitophagic flux, leading to the buildup of damaged mitochondria and ROS. Pharmacological intervention with mitoTEMPO alleviated mitochondrial dysfunction, while clioquinol restored lysosomal function and improved mitophagy. Additionally, the cGAS-STING signaling pathway was found to regulate inflammation in ATB-DILI, with both mitoTEMPO and clioquinol alleviating its effects. These findings elucidate the crucial impact of lysosome-mediated mitophagy dysfunction and mitochondrial ROS in ATB-DILI, highlighting potential therapeutic targets to enhance liver protection during anti-TB treatment.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114984"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170549","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":"Epigollatecatechin gallate alleviates rheumatoid arthritis through PI3K-Akt pathway by inhibiting FLT1","authors":"Li Wang,&nbsp;Beibei Zhao,&nbsp;Jing Wang,&nbsp;Dongfeng Zhang,&nbsp;Ruixiao Ma,&nbsp;Tianyi Zhang,&nbsp;Yijin Qi,&nbsp;Yemeng Sheng,&nbsp;Baoping Hu,&nbsp;Tianbo Jin","doi":"10.1016/j.intimp.2025.114958","DOIUrl":"10.1016/j.intimp.2025.114958","url":null,"abstract":"<div><h3>Background</h3><div>Rheumatoid arthritis (RA) is a chronic inflammatory disease. Ershiwuwei Luyue Pill (ELP), a Tibetan medicine prescription, is one of the most commonly used treatments for wind dampness and joint pain. However, its detailed mechanism of action remains unclear.</div></div><div><h3>Methods</h3><div>Using network pharmacology approaches, the primary active compounds, potential targets, and related signaling pathways of ELP in the treatment of RA were evaluated. The binding action between the key active ingredient (−)-epigallocatechin-3-gallate (EGCG) and the key target fms related receptor tyrosine kinase 1 (<em>FLT1</em>) was verified through molecular docking. Lipopolysaccharide (LPS)-induced HLFS-RA cell injury model and collagen-induced arthritis mouse model (CIA model) were established. Cell viability, invasion and migration were tested by the CCK8 kit, Transwell assay, and scratch assay, respectively. The expression of inflammatory factors, PI3K/AKT pathway-related proteins, and <em>FLT1</em> was assessed by RT-qPCR and western blot.</div></div><div><h3>Results</h3><div>Network pharmacology revealed the strong binding activity between EGCG, a primary active component of ELP, and the key target <em>FLT1</em> in the treatment of RA. <em>In vitro</em> and <em>in vivo</em> experimental data showed that EGCG treatment markedly reduced the expression of <em>FLT1</em> and suppressed the expression of PI3K pathway-related proteins. <em>FLT1</em> knockdown or EGCG treatment could inhibit cell viability, invasion and migration, as well as the expression of inflammatory factors, but accelerate cell apoptosis. <em>In vivo</em> experiments also confirmed that EGCG might regulate the PI3K pathway through <em>FLT1</em>.</div></div><div><h3>Conclusion</h3><div>EGCG, a key component of ELP, has significant therapeutic effects on RA by suppressing the PI3K/AKT signaling pathway and downregulating <em>FLT1</em> gene expression, thereby exhibiting anti-inflammatory effects.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114958"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170547","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":"Melatonin modulates mitochondrial function and inhibits atherosclerosis progression through NRF2 activation and OPA1 inhibition","authors":"Chengbo Lu ,&nbsp;Quan Lin ,&nbsp;Xiaoli Guo ,&nbsp;Tan Luo ,&nbsp;Han Zhou ,&nbsp;Ziteng Cai ,&nbsp;Chaonan Peng ,&nbsp;Guangyuan Yang ,&nbsp;Weiqun Wang","doi":"10.1016/j.intimp.2025.114960","DOIUrl":"10.1016/j.intimp.2025.114960","url":null,"abstract":"<div><h3>Background</h3><div>Atherosclerosis (AS), a major cardiovascular disease, is characterized by chronic inflammation and oxidative stress. Melatonin (MLT) has emerged as a potential therapeutic agent due to its anti-inflammatory and antioxidant properties, although the specific mechanisms underlying its action, especially as far as mitochondrial function in AS is concerned, have yet to be fully elucidated.</div></div><div><h3>Methods</h3><div>In this study, ApoE^−/− mice were fed a high-fat diet with or without MLT treatment. Aortic tissues were analyzed using hematoxylin and eosin, Masson staining, qPCR, and immunofluorescence. Oxidized low-density lipoprotein-treated RAW264.7 macrophages were assessed for AS progression, mitochondrial function, and oxidative stress using electron microscopy, Seahorse analysis, and molecular docking.</div></div><div><h3>Results</h3><div>MLT treatment significantly reduced atherosclerotic plaque formation, systemic and mitochondrial oxidative stress, and inflammation. MLT treatment was found to enhance mitochondrial function through upregulating the expression of key regulators of mitochondrial biogenesis and the activity of mitochondrial respiratory chain complexes, whereas markers of mitochondrial fusion [for example, optic atrophy protein 1 (OPA1)] were downregulated. Mechanistically, MLT was shown to directly interact with nuclear factor erythroid 2-related factor 2 (NRF2), thereby activating its antioxidant pathway, which in turn regulated mitochondrial function. Additionally, OPA1 was identified as a downstream target of MLT, and its inhibition improved mitochondrial function and reduced inflammation.</div></div><div><h3>Conclusion</h3><div>This study is the first to elucidate that MLT synergistically ameliorates mitochondrial dysfunction through dual mechanisms—activating the NRF2 antioxidant pathway and suppressing OPA1-mediated mitochondrial fusion—providing novel therapeutic targets for AS.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114960"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144178379","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":"Type I and II pili mediate Streptococcus pneumoniae invasion into human blood-brain barrier-derived cells through extracellular matrix protein receptors and different endocytosis pathways","authors":"Sui-Ning Chen ,&nbsp;Yu-Jin Wang ,&nbsp;Meng-Jie Li ,&nbsp;Yi-Qiong Xing ,&nbsp;Meng-Yi Guo ,&nbsp;Jie Yan ,&nbsp;Ai-Hua Sun","doi":"10.1016/j.intimp.2025.114918","DOIUrl":"10.1016/j.intimp.2025.114918","url":null,"abstract":"<div><div><em>Backgroud: Streptococcus pneumoniae</em> is the most common pathogen of bacterial meningitis, but mechanisms of this pathogen invading blood-brain barrier (BBB) remain unknown.</div><div><em>Methods:</em> Invasion of <em>S. pneumoniae</em> strains and microbeads coated with recombinant pilin, rRrgA-B or rPitB, into human BBB-derived brain microvascular endothelial cells (HBMECs), brain vascular pericytes (HBVPs), and astrocytes (HAs) by laser scanning confocal microscopy (LSCM). Fibronectin (FN), laminin (LN), and collagen-1/3/4 (COL-1/3/4) in the extracellular matrix (ECM) were detected by LSCM and flow cytometry. rRrgA-B and rPitB binding to the ECM proteins were identified using surface plasmon resonance. Pneumococcal endocytosis pathways, Ca²⁺ level, microfilament (MF) and microtubule (MT) polymerization in the cells were determined by LSCM-based inhibition assay.</div><div><em>Results:</em> Type I/II pili-positive <em>S. pneumoniae</em> SP007 displayed natably stronger invasiveness into the cells than pilus-free <em>S. pneumoniae</em> ATCC49619. rRrgA-B-/rPitB-coated microbeads also exhibited invasion ability. HBMECs express FN, LN, and COL1, while HBVPs and HAs express all the ECM proteins. rRrgA-B and rPitB displayed a rapid binding to all the ECM proteins with K_D values ranging from 3.25 × 10⁻⁷ to 9.58 × 10⁻⁸ M. Intracellular free Ca²⁺ increase and MF-dependent cytoskeleton rearrangement occurred during invasion of the pneumococcal strains and rRrgA-B-/rPitB-coated microbeads. Invasion of the strains and rRrgA-B-/rPitB-coated microbeads into these cells involved integrin (ITG), focal adhesion kinase (FAK), Rho-associated coiled-coil forming kinase (ROCK) or phosphatidylinositol-3-kinase (PI3K), clathrin (CLN)-, caveolae (CAV)- or macropinocytosis (MPC)-dependent endocytosis.</div><div><em>Conclusion:</em> Type I and II pili play important roles to mediate <em>S. pneumoniae</em> invasion into BBB-direived cells through FN/LN/COL1-ITG-FAK/ROCK-Ca²⁺-MF-CLN/CAV/MPC- or FN/LN/COL1/3/4-ITG-FAK/PI3K-Ca²⁺-MF-CLN/CAV-dependent endocytosis pathways to cause meningitis.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114918"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170443","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":"Acetylation of FABP3 alleviates radioimmunotherapy-induced cardiomyocyte senescence by modulating long-chain polyunsaturated fatty acid metabolism","authors":"Yuxi Luo ,&nbsp;Ying Yu ,&nbsp;Fujuan Zeng ,&nbsp;Yali Yi ,&nbsp;Zhiqin Lu ,&nbsp;Bilin Lin ,&nbsp;Leifeng Chen ,&nbsp;Zhimin Zeng ,&nbsp;Daya Luo ,&nbsp;Anwen Liu","doi":"10.1016/j.intimp.2025.114912","DOIUrl":"10.1016/j.intimp.2025.114912","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;The combination of thoracic radiotherapy and immunotherapy (radioimmunotherapy) has shown significant antitumor efficacy but is associated with increased cardiotoxicity, the mechanisms of which remain poorly understood.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;A total of 72 male C57BL/6 J mice were employed to establish the radioimmunotherapy-induced cardiac injury model, with 18 mice allocated to each of four groups, including the IR group (single-dose 16 Gy cardiac irradiation), ICI group (PD-1 inhibitor 200 μg every 3 days), iRT group (16 Gy cardiac irradiation combined with PD-1 inhibitor), and Control group (IgG). Cardiac function and myocardial senescence were assessed at 28 days, 3 months, and 5 months post-intervention. Additionally, myocardial tissue transcriptomics, non-targeted metabolomics, and acetylated proteomics were performed at 28 days post-intervention, integrated with molecular experiments to investigate the mechanisms of cardiomyocyte senescence. H9C2 cardiomyocytes with FABP3 K45 acetylation-mimetic (K45Q), empty vector (EV), and non-acetylatable (K45R) mutant were used for functional validation.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Combined radioimmunotherapy significantly exacerbated cardiac dysfunction and cardiomyocyte senescence in murine models, manifested with elevated serum levels of cardiac injury biomarkers of cTnI and NT-proBNP, reduced LVEF and LVFS, aggravated myocardial histopathological changes characterized by enhanced inflammatory infiltration, interstitial edema, and myocardium structure disorder in iRT group compared to the other three groups. Concomitantly, compared with other groups, the senescence-associated markers (p16, p21, and SASP factors) in the myocardial tissues of the iRT group were markedly upregulated from 28 days to 5 months. By integrating transcriptomic and non-targeted metabolomics analyses, as well as molecular experiments, we revealed that radioimmunotherapy resulted in dysregulated myocardial metabolism by suppressing ATP production, promoting lipid droplet accumulation, mitochondrial dysfunction, and fatty acid metabolism alterations, particularly involving long-chain polyunsaturated fatty acid (PUFAs) metabolism. Acetylome profiling identified a significant increase in FABP3 K45 acetylation (log&lt;sub&gt;2&lt;/sub&gt;FC = 8.73, &lt;em&gt;P&lt;/em&gt; &lt; 0.05) in iRT vs. Control group, with acute-phase elevation (28 days, &lt;em&gt;P&lt;/em&gt; &lt; 0.001) and chronic-phase reduction (3 months, &lt;em&gt;P&lt;/em&gt; &lt; 0.001). Functional validation in H9C2 cardiomyocytes demonstrated that, compared to EV and K45R groups, FABP3 K45Q attenuated cellular senescence, enhanced mitochondrial oxidative phosphorylation, fatty acid metabolism, and ATP production, while attenuated ROS generation, lipid droplet accumulation, and glycolysis. Metabolomic analysis also revealed the acetylation of FABP3 K45 was significantly associated with the synthesis or accumulation of PUFAs, such as arachidonic acid and linolei","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114912"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170550","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":"Targeting SPP1+ macrophages via the SPP1-CD44 axis reveals a key mechanism of immune suppression and tumor progression in ovarian cancer","authors":"Lisha Hou ,&nbsp;Mei Jiang ,&nbsp;Yue Li ,&nbsp;Jin Cheng ,&nbsp;Fei Liu ,&nbsp;Xiaoyang Han ,&nbsp;Jiahao Guo ,&nbsp;Lei Feng ,&nbsp;Zhefeng Li ,&nbsp;Junjie Yi ,&nbsp;Xiaoting Zhao ,&nbsp;Yan Gao ,&nbsp;Wentao Yue","doi":"10.1016/j.intimp.2025.114906","DOIUrl":"10.1016/j.intimp.2025.114906","url":null,"abstract":"<div><div>Tumor-associated macrophages (TAMs) play a pivotal role in immune suppression, tumor progression, and metastasis within the tumor microenvironment (TME) of ovarian cancer. While TAMs are known to promote T-cell dysfunction, the precise molecular mechanisms governing this process remain poorly understood. Here, we performed an integrated analysis of six high-grade serous ovarian cancer (HGSOC) single-cell sequencing datasets to investigate the molecular and functional diversity of TAMs in HGSOC. We identified an SPP1⁺ TAM subpopulation enriched in HGSOC and strongly associated with poor prognosis. These macrophages promoted T-cell exhaustion <em>via</em> the SPP1-CD44 axis, which emerged as the principal mediator of immune suppression. Functional assays demonstrated that SPP1 secreted by TAMs drove T-cell exhaustion, weakening anti-tumor immunity. Blocking either SPP1 or CD44 effectively reversed T-cell exhaustion, restored CD8⁺ T-cell functionality, and suppressed tumor growth <em>in vivo</em>. Furthermore, molecular docking and dynamics simulations identified nilotinib as a potential SPP1 inhibitor, exhibiting strong binding affinity and stability. <em>In vitro</em> assays confirmed that nilotinib reduced PD-1 expression in Jurkat cells induced by M2-type macrophages, underscoring its therapeutic potential in reversing T-cell exhaustion in ovarian cancer. The research demonstrates that SPP1⁺ TAMs drive immune suppression and T-cell exhaustion in ovarian cancer <em>via</em> the SPP1-CD44 axis, highlighting this pathway as a promising therapeutic target for reprogramming the immune microenvironment and improving patient outcomes.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114906"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170442","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":"Mefunidone treats pulmonary fibrosis by targeting SDH to regulate fibro-promoting macrophages","authors":"Xiangyu Zhang ,&nbsp;Yijun He ,&nbsp;Lingzhi Long ,&nbsp;Guoliang Jiang ,&nbsp;Tingting Yao ,&nbsp;Xiaoyun Cheng ,&nbsp;Zhangzhe Peng ,&nbsp;Gaoyun Hu ,&nbsp;Lijian Tao ,&nbsp;Jie Meng","doi":"10.1016/j.intimp.2025.114971","DOIUrl":"10.1016/j.intimp.2025.114971","url":null,"abstract":"<div><h3>Background and objective</h3><div>Pulmonary fibrosis, a pathological process where the extracellular matrix overly deposits in lung tissue because of various pathogenic factors, leads to lung structure damage and function decline. Idiopathic pulmonary fibrosis (IPF) has a poor prognosis and high mortality, lacking effective drug treatments. Mefunidone (MFD), a new small-molecule compound, showed therapeutic effects on it in previous studies, but its specific molecular target is unknown. This study aims to clarify MFD's target and its potential mechanism. By exploring this, we hope to offer new insights and potential solutions for treating IPF and improving patients' outcomes.</div></div><div><h3>Methods</h3><div>Mice with pulmonary fibrosis induced by bleomycin (BLM) were used as experimental models. MFD was administered by gavage. The changes in inflammation and fibrosis were evaluated through histopathological examinations. Subsequently, single-cell sequencing technology was used to explore how MFD affects the phenotype of pro-fibrotic macrophages, and verification was carried out <em>in vitro</em> to prove that MFD treats pulmonary fibrosis by influencing the phenotype of pro-fibrotic macrophages.</div></div><div><h3>Result</h3><div>MFD can inhibit the generation of succinate by binding and inhibiting the activity of succinate dehydrogenase (SDH). MFD can also inhibit the transformation of MMP12⁺CCL2⁺ profibrotic macrophages in the BLM pulmonary fibrosis model. Treatment with succinate can induce the transformation of macrophages into MMP12⁺CCL2⁺ profibrotic macrophages, and this induction depends on the succinate-specific receptor GPR91.</div></div><div><h3>Conclusion</h3><div>Our research results have revealed for the first time that MFD can treat pulmonary fibrosis by targeting SDH and regulating the transformation of MMP12⁺CCL2⁺ profibrotic macrophages.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"160 ","pages":"Article 114971"},"PeriodicalIF":4.8,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170445","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}