International immunopharmacology最新文献

{"title":"Heterophyllin B alleviates cognitive disorders in APP/PS1 model mice via the spleen-gut microbiota-brain axis","authors":"Jiahui Jiang ,&nbsp;Jiahang Deng ,&nbsp;Yuntao Zhao ,&nbsp;Shuai Zhao ,&nbsp;Nasar Ullah Khan Niazi ,&nbsp;Yuewei Ge ,&nbsp;Zhiyou Yang","doi":"10.1016/j.intimp.2025.114591","DOIUrl":"10.1016/j.intimp.2025.114591","url":null,"abstract":"<div><div><em>Background:</em> Accumulating evidence implicates both the brain-spleen axis and the gut microbiota-brain axis in Alzheimer's disease (AD) pathogenesis. While our previous work demonstrated heterophyllin B (HB) rectifies splenic Th1/Th2 imbalance and ameliorates cognitive deficits in Aβ1–42-induced AD mice, its potential modulation of the vagus nerve-spleen circuit remains unexplored.</div><div><em>Methods:</em> Using 8-month-old male APP/PS1 mice with/without splenic denervation (SD), we systematically investigated HB's therapeutic mechanisms via the spleen-gut microbiota-brain axis. Cognitive function was assessed through novel object recognition (ORT) and object location memory (OLT) tests. Immunofluorescence (IF) and enzyme-linked immunosorbent assay (ELISA) were employed to analyze Aβ plaques, phosphorylated tau (p-Tau) levels, and associated neuroinflammatory responses. Flow cytometry was utilized to examine the subtypes of splenic lymphocytes. Hematoxylin and eosin (H&amp;E) staining, along with immunohistochemical (IHC) experiments, was conducted to evaluate the protective effects of HB on the intestinal barrier. Gut microbiota composition was analyzed using 16S rRNA sequencing.</div><div><em>Results</em>: HB administration significantly improved cognitive performance (ORT discrimination index: +28.7 %; OLT discrimination index: +26.6 %), reduced brain and serum Aβ1–42 and p-Tau levels, downregulated the Th1/Th2 ratio in the spleen, and alleviated intestinal permeability and neuroinflammation, which were abolished in SD APP/PS1 mice. Gut microbiota shifts showed HB-induced enrichment of cognition-associated <em>Dubosiella</em> and <em>Muribaculaceae</em>, with concurrent suppression of pathogenic <em>Lachnospiraceae_NK4A136</em> and <em>ASF356</em>.</div><div><em>Conclusion</em>: This study provides first evidence that HB ameliorates AD pathology through vagus nerve-dependent regulation of the spleen-gut microbiota-brain axis, establishing its multimodal therapeutic potential for neural-immune-gut circuit modulation in neurodegenerative diseases<strong>.</strong></div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"154 ","pages":"Article 114591"},"PeriodicalIF":4.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785538","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":"Role of m7G modification regulators as biomarkers in gastric cancer subtyping and precision immunotherapy","authors":"Fa Ling ,&nbsp;Huolun Feng ,&nbsp;Sifan Wu ,&nbsp;Dandan Zhu ,&nbsp;Yinfeng Chen ,&nbsp;Jianlong Zhou ,&nbsp;Jiayi Lai ,&nbsp;Xing Huang ,&nbsp;Tieying Hou ,&nbsp;Yong Li","doi":"10.1016/j.intimp.2025.114594","DOIUrl":"10.1016/j.intimp.2025.114594","url":null,"abstract":"<div><div>This study investigated the role of N7-methylguanosine (m7G) modification regulators as biomarkers in subtyping and precision immunotherapy of gastric cancer (GC). Through multi-omics analyses, including RNA sequencing, proteomics, and single-cell measurement, the study revealed heterogeneity in the m7G regulatory landscape among GC patients. Three m7G subtypes were identified, each with distinct pathways and phenotypes. Patients with low m7Gscores, based on an established scoring system, showed better survival outcomes and increased antitumor immune cell infiltration, as well as higher tumor mutation loads and lower PD-L1 expression. The predictive value of m7Gscore was confirmed in two immunotherapy cohorts. These findings highlight the potential of m7G modification in shaping the tumor microenvironment and provide new insights for immunotherapeutic strategies in GC patients.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"154 ","pages":"Article 114594"},"PeriodicalIF":4.8,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143785539","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":"Low-frequency ultrasound alleviates pulmonary inflammation induced by Klebsiella pneumoniae in mice by inhibiting the TNFR1/NF-κB pathway","authors":"Wenxin Liang ,&nbsp;Yulong Chi ,&nbsp;Beibei Liang ,&nbsp;Guanshuang Fu ,&nbsp;Kaicheng Yan ,&nbsp;Guanxuanzi Zhang ,&nbsp;Yun Cai","doi":"10.1016/j.intimp.2025.114574","DOIUrl":"10.1016/j.intimp.2025.114574","url":null,"abstract":"<div><h3>Background</h3><div>Therapeutic ultrasound has been found to promote tissue healing and reduce inflammation in non-infectious diseases, but its efficacy in infectious inflammation remains unclear. Here, we employ the mice pneumonia model to explore the anti-inflammatory effects of low-frequency ultrasound (LFU) and elucidate its potential molecular mechanisms.</div></div><div><h3>Methods</h3><div>Pneumonia in mice was induced by intratracheal instillation of 100 μL of a 4.5 × 10⁸ CFU/mL <em>Klebsiella pneumoniae</em> (Kp) bacterial suspension. A single LFU treatment (29.36 kHz, 270 mW/cm², 10 min) was applied to the chest of mice at 6 or 48 h after infection. Biological samples were collected for gene, protein, and cellular experiments.</div></div><div><h3>Results</h3><div>LFU demonstrated good anti-inflammatory effects in mice during the recovery phase of Kp infection (48 h after infection). Although LFU alone had no bactericidal effects, it slightly reduced the pathological score of lung injury and significantly decreased the infiltration of CD45⁺ leukocytes. Additionally, the protein levels of TNF-α, GM-CSF and COX-2 in the bronchoalveolar lavage fluid were significantly reduced. Bulk RNA-sequencing results showed that the TNF receptor (TNFR)/NF-κB pathway was up-regulated after Kp infection, which was suppressed after LFU treatment. Western blot and immunofluorescence revealed LFU significantly reduced the protein levels of TNFR1, p-p65, and nuclear p65. The anti-inflammatory effect of LFU was comparable to a 20 mg/kg NF-κB inhibitor and superior to a 15 mg/kg TNFR antagonist.</div></div><div><h3>Conclusion</h3><div>LFU exerts anti-inflammatory effects by inhibiting the TNFR1/NF-κB pathway during the recovery period of Kp infection, reducing inflammatory transcription and thereby decreasing the release of inflammatory factors.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"154 ","pages":"Article 114574"},"PeriodicalIF":4.8,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777407","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":"β-Hydroxybutyrate aggravates LPS-induced inflammatory response in bovine endometrial epithelial cells by activating the oxidative stress/NF-κB signaling pathway","authors":"Wanghao Yang ,&nbsp;Fengbo Wang ,&nbsp;Jijun Liu ,&nbsp;Xuerong Wang ,&nbsp;Haisen Zhang ,&nbsp;Dengke Gao ,&nbsp;Aihua Wang ,&nbsp;Yaping Jin ,&nbsp;Huatao Chen","doi":"10.1016/j.intimp.2025.114609","DOIUrl":"10.1016/j.intimp.2025.114609","url":null,"abstract":"<div><div>Ketosis, a metabolic disorder characterized by elevated levels of ketone bodies in the blood or urine, is known to impair the health and productivity of dairy cows, leading to substantial economic losses in the dairy industry. When ketosis occurs in dairy cows, the levels of β-hydroxybutyrate (BHBA), an abundant form of ketone bodies, in the blood increase significantly. Elevated BHBA levels have been shown to negatively impact reproductive performance and increase the incidence of periparturient diseases in dairy cows, including mastitis and endometritis. However, the role of BHBA in the development of endometritis in dairy cows and its underlying mechanisms remain largely unclear. The present study was designed to investigate the specific role of BHBA in the development of endometritis using an inflammatory response model of the bovine endometrial epithelial cell line (BENDs). <em>Escherichia coli</em> lipopolysaccharide (LPS) treatment (1 μg/mL) significantly increased the expression levels of <em>interleukin</em> (<em>IL</em>)<em>-6</em> and <em>IL-1β</em>, as well as the phosphorylation of p65 and IκB in BENDs. In addition, co-treatment with BHBA (2.4 mM) and LPS (1 μg/mL) significantly increased the expression levels of proinflammatory cytokines (<em>IL-6</em>, <em>IL-1β</em>, and <em>IL-8</em>), as well as the phosphorylation of p65 and IκB, compared to the LPS-only treatment group. Immunofluorescence staining showed that the addition of LPS altered the nuclear localization of p65, and co-treatment with BHBA and LPS further promoted the translocation of p65 to the nucleus. Additionally, the addition of BHBA significantly increased the levels of oxidation indicators (MDA), whereas the levels of antioxidative indicators, including <em>heme oxygenase-1</em> (<em>HO-1</em>) and <em>catalase</em> (<em>CAT</em>), were markedly decreased in BENDs. As a representative antioxidant, <em>N</em>-acetylcysteine (NAC) treatment significantly reduced the phosphorylation of p65 and IκB in the BHBA and LPS co-treatment group. SC75741, an NF-κB signaling pathway inhibitor, significantly decreased the expression levels of proinflammatory cytokines (<em>IL-6</em>, <em>IL-1β</em>, <em>IL-8</em>, and <em>CCL5</em>) in the BHBA and LPS co-treatment group. In summary, the current study demonstrates that BHBA aggravates LPS-induced inflammatory response in BENDs through the activation of oxidative stress/NF-κB signaling pathway, unravelling the mechanism by which BHBA exacerbates the inflammatory response in the BENDs of dairy cattle. This study elucidates the role of ketosis and its key metabolite BHBA in the pathogenesis of endometritis in dairy cows, providing valuable insights for understanding this pathological process.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"154 ","pages":"Article 114609"},"PeriodicalIF":4.8,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777412","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":"Immune modulation for the patterns of epithelial cell death in inflammatory bowel disease","authors":"Yuting Jiang ,&nbsp;Jie Chen ,&nbsp;Yaoyao Du ,&nbsp;Minwei Fan ,&nbsp;Lan Shen","doi":"10.1016/j.intimp.2025.114462","DOIUrl":"10.1016/j.intimp.2025.114462","url":null,"abstract":"<div><div>Inflammatory bowel disease (IBD) is an inflammatory disease of the intestine whose primary pathological presentation is the destruction of the intestinal epithelium. The intestinal epithelium, located between the lumen and lamina propria, transmits luminal microbial signals to the immune cells in the lamina propria, which also modulate the intestinal epithelium. In IBD patients, intestinal epithelial cells (IECs) die dysfunction and the mucosal barrier is disrupted, leading to the recruitment of immune cells and the release of cytokines. In this review, we describe the structure and functions of the intestinal epithelium and mucosal barrier in the physiological state and under IBD conditions, as well as the patterns of epithelial cell death and how immune cells modulate the intestinal epithelium providing a reference for clinical research and drug development of IBD. In addition, according to the targeting of epithelial apoptosis and necroptotic pathways and the regulation of immune cells, we summarized some new methods for the treatment of IBD, such as necroptosis inhibitors, microbiome regulation, which provide potential ideas for the treatment of IBD. This review also describes the potential for integrating AI-driven approaches into innovation in IBD treatments.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"154 ","pages":"Article 114462"},"PeriodicalIF":4.8,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777406","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":"Ubiquitin-conjugating enzyme E2S (UBE2S) as a prognostic biomarker and regulator of tumorigenesis in osteosarcoma","authors":"Binfeng Liu ,&nbsp;Chenbei Li ,&nbsp;Shasha He ,&nbsp;Zhaoqi Li ,&nbsp;Hua Wang ,&nbsp;Chengyao Feng ,&nbsp;Zijian Xiong ,&nbsp;Chao Tu ,&nbsp;Deye Song ,&nbsp;Zhihong Li","doi":"10.1016/j.intimp.2025.114545","DOIUrl":"10.1016/j.intimp.2025.114545","url":null,"abstract":"<div><div>Ubiquitin-conjugating enzyme E2S (UBE2S) is a member of ubiquitin conjugating enzymes with unclear association with osteosarcoma (OS). This study aimed to assess UBE2S's predictive value in OS using data from TCGA and GEO databases. Kaplan-Meier survival analysis and ROC curves were used for prognostic evaluation, and a nomogram was developed for prognostic prediction. Potential biological functions, pathways, and correlations with tumor immune microenvironment, immunotherapy response, and drug sensitivity were analyzed. UBE2S overexpression was linked to poor prognosis, and the nomogram effectively predicted OS survival outcomes. UBE2S was found to impact tumorigenesis pathways, immune landscape, and treatment sensitivity in OS. Transcriptome sequencing, RT-qPCR, Western Blotting, and immunohistochemistry confirmed that UBE2S is abnormally overexpressed in OS. Additionally, a series of in vitro experiments showed that UBE2S knockdown reduced OS cell proliferation and migration while promoting apoptosis. In vivo experiments also confirmed that UBE2S knockdown could inhibit OS cell growth. In summary, our research demonstrates that UBE2S is a reliable prognostic factor for OS. Its abnormal overexpression enhances OS proliferation and migration, indicating its significance for future personalized treatment strategies in OS.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"154 ","pages":"Article 114545"},"PeriodicalIF":4.8,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777408","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":"Loss of macrophage fibroblast growth factor 12 attenuates cardiac fibrosis in pressure-overloaded myocardium","authors":"Santie Li ,&nbsp;Mei Xue ,&nbsp;Junjie Lu ,&nbsp;Lingli Chen ,&nbsp;Sihang Li ,&nbsp;Leyi Shen ,&nbsp;Junbo Ye ,&nbsp;Qiaoyan Shi ,&nbsp;Meifan Jiang ,&nbsp;Kunxuan Zhu ,&nbsp;Junfu Fan ,&nbsp;Gaozan Tong ,&nbsp;Xiaojing Yi ,&nbsp;Xu Wang ,&nbsp;Weitao Cong ,&nbsp;Xueqiang Guan","doi":"10.1016/j.intimp.2025.114614","DOIUrl":"10.1016/j.intimp.2025.114614","url":null,"abstract":"<div><h3>Background</h3><div>Cardiac fibrosis, a leading cause of death worldwide, plays a functional role in the development of heart failure. Unfortunately, there are currently no therapeutic strategies in clinical practice that can specifically attenuate the activation of cardiac fibroblasts, the effector cells of fibrosis in the heart. In this study, we aimed to identify a novel approach to target myocardial fibrosis through the crosstalk between macrophages and fibroblasts.</div></div><div><h3>Methods</h3><div>We investigated the expression of fibroblast growth factor 12 (FGF12), a novel regulator of macrophage activation, in both human subjects and mouse models. We also generated myeloid cell-specific FGF12 knockout mice to determine the role of FGF12 in cardiac fibrosis. For <em>in vitro</em> studies, we isolated mouse primary bone marrow-derived macrophages (BMDMs) and cardiac fibroblasts to explore the mechanism by which FGF12 controls macrophage polarization and fibroblast activation.</div></div><div><h3>Results</h3><div>We found that FGF12 expression was significantly upregulated in both human failing hearts and mouse pressure-overloaded myocardium. RNA sequencing revealed that FGF12 upregulation was associated with fibrosis progression, oxidative stress response, and macrophage activation in mouse heart tissues. Myeloid-specific knockout of FGF12 markedly attenuated pressure overload-induced myocardial fibrosis in our mouse models. We observed that FGF12 significantly affects interleukin-4-stimulated M2 polarization in BMDMs. Conditioned medium from FGF12 knockdown or overexpressed BMDMs also influenced cardiac fibroblast activation, primarily by affecting reactive oxygen species (ROS) accumulation in cardiac fibroblasts. Furthermore, we demonstrated that FGF12 controls BMDM M2 polarization through the SOCS/STAT pathway.</div></div><div><h3>Conclusions</h3><div>FGF12 is a novel regulator of myocardial fibrosis, acting through the modulation of crosstalk between macrophages and fibroblasts. Therapeutic approaches targeting FGF12 may represent a potential strategy to ameliorate cardiac fibrosis or other fibrosis-related diseases in the future.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"154 ","pages":"Article 114614"},"PeriodicalIF":4.8,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777410","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":"Compound J27 alleviates high-fat diet-induced metabolic dysfunction-associated steatotic liver disease by targeting JNK","authors":"Jiaxi Ye ,&nbsp;Weiwei Zhu ,&nbsp;Yaqian Cui ,&nbsp;Qianhui Zhang ,&nbsp;Yongqiang Xiong ,&nbsp;Leiming Jin ,&nbsp;Ao Wang ,&nbsp;Mengsha Lin ,&nbsp;Hui Dong ,&nbsp;Guang Liang ,&nbsp;Xiang Hu ,&nbsp;Wu Luo","doi":"10.1016/j.intimp.2025.114570","DOIUrl":"10.1016/j.intimp.2025.114570","url":null,"abstract":"<div><h3>Background</h3><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most characteristic form of liver diseases. As the member of MAPK family, the cJun-N-terminal-kinase (JNK) plays a crucial role in the pathogenesis of MASLD. A small molecule compound, J27, has demonstrated strong anti-inflammatory effects by inhibiting JNK phosphorylation, but its therapeutic potential in MASLD remains unclear.</div></div><div><h3>Methods</h3><div>To evaluate the effect of J27, we used a high-fat diet (HFD)-induced MASLD mouse model with or without J27 treatment. Pathological changes were assessed through tissue staining, biochemical analysis, and other assays. <em>In vitro</em>, J27's effects were tested on macrophages, hepatocytes, and co-culture systems under palmitic acid stimulation.</div></div><div><h3>Results</h3><div>J27 significantly reduced HFD-induced hepatic steatosis, liver injury, insulin resistance, and inflammatory responses by targeting JNK both <em>in vivo</em> and <em>in vitro</em>. On one hand, J27 blocked JNK activation, thereby improving insulin signaling and alleviating metabolic dysfunction in hepatocytes. On the other hand, J27 inhibited the inflammatory response in macrophages by disrupting the JNK/NF-κB axis, which, through cell-cell communication, further reduced hepatocyte injury.</div></div><div><h3>Conclusions</h3><div>J27, as a potent JNK inhibitor, markedly reduced HFD-induced MASLD, suggesting it as a promising therapeutic candidate for this disease.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"154 ","pages":"Article 114570"},"PeriodicalIF":4.8,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777411","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":"NLRP3 Inflammasome-mediated pyroptosis in acute lung injury: Roles of main lung cell types and therapeutic perspectives","authors":"Jing Wang ,&nbsp;Lu-Lu Li ,&nbsp;Zhen-Ao Zhao ,&nbsp;Chun-Yu Niu ,&nbsp;Zi-Gang Zhao","doi":"10.1016/j.intimp.2025.114560","DOIUrl":"10.1016/j.intimp.2025.114560","url":null,"abstract":"<div><div>The NLRP3 inflammasome plays a pivotal role in the pathogenesis of acute lung injury (ALI) by regulating pyroptosis, a highly inflammatory form of programmed cell death. NLRP3-mediated pyroptosis leads to alveolar epithelial cell injury, increased pulmonary microvascular endothelial permeability, excessive alveolar macrophage activation, and neutrophil dysfunction, collectively driving ALI progression. In addition to the classical NLRP3-dependent pathway, the non-canonical pyroptosis pathway (caspase-4/5/11) also contributes to ALI by inducing pyroptotic cell death in AECs and ECs, further amplifying NLRP3 activation through damage-associated molecular patterns (DAMP) release. Moreover, neutrophils (NE) pyroptosis exhibits dual roles in ALI, as it enhances pathogen clearance but also exacerbates excessive inflammation and tissue damage, highlighting the complexity of its regulation. Targeting the NLRP3 inflammasome and pyroptotic pathways has emerged as a promising therapeutic strategy for ALI. Various NLRP3 inhibitors (e.g., MCC950, CY-09, OLT1177) and pyroptosis inhibitors have demonstrated significant anti-inflammatory and tissue-protective effects in preclinical models. However, the clinical translation of NLRP3-targeted therapies remains challenging due to off-target effects, potential immunosuppression, lack of patient stratification strategies, and compensatory activation of alternative inflammasomes (e.g., AIM2, NLRC4). Future studies should focus on optimizing the selectivity of NLRP3 inhibitors, developing personalized therapeutic approaches, and exploring combination strategies to enhance their clinical applicability in ALI.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"154 ","pages":"Article 114560"},"PeriodicalIF":4.8,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777494","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":"GTS-21 alleviates sepsis-induced atrial fibrillation susceptibility by modulating macrophage polarization and Neuregulin-1 secretion","authors":"Jiabao Zhou ,&nbsp;Keke Wu ,&nbsp;Yingxu Ma ,&nbsp;Jiayi Zhu ,&nbsp;Yong Zhou ,&nbsp;Zixi Zhang ,&nbsp;Fanqi Li ,&nbsp;Gaoming Zeng ,&nbsp;Shunyi Li ,&nbsp;Siyuan Tan ,&nbsp;Yusha Zhang ,&nbsp;Cancan Wan ,&nbsp;Tao Tu ,&nbsp;Qiuzhen Lin ,&nbsp;Qiming Liu","doi":"10.1016/j.intimp.2025.114561","DOIUrl":"10.1016/j.intimp.2025.114561","url":null,"abstract":"<div><h3>Objective</h3><div>Sepsis-induced atrial fibrillation (AF) is driven by systemic inflammation and macrophage-mediated atrial remodeling, with proinflammatory M1 macrophages playing a key role. This study investigates whether GTS-21, an α7nAChR agonist, can reduce AF susceptibility by promoting macrophage polarization towards the anti-inflammatory M2 phenotype.</div></div><div><h3>Methods</h3><div>A mouse model of lipopolysaccharide (LPS) (10 mg/kg)-induced sepsis was used to explore the relationship between atrial inflammation and AF. GTS-21 (20 mg/kg) was administered to assess its impact on 48-h survival and AF incidence. Cardiac function was evaluated using echocardiography. Markers of myocardial injury, including CK-MB, LDH, and cTnI, were measured. Macrophage polarization and atrial inflammation were assessed using immunofluorescence, flow cytometry, RT-qPCR, and western blotting. Oxidative stress and mitochondrial function were evaluated using reactive oxygen species (ROS) measurements, electron microscopy, and mitochondrial protein expression analysis. Calcium dynamics were studied using western blotting and confocal microscopy.</div></div><div><h3>Results</h3><div>In LPS-induced septic mice, GTS-21 improved 48-h survival rates and reduced the induction rate and duration of AF (<em>P</em> &lt; 0.05). Echocardiography showed a preserved left ventricular ejection fraction and enhanced diastolic function. Mechanistically, it promoted M2 macrophage polarization, inhibited the NF-κB P65/NLRP3/C-caspase 1 pathway to reduce IL-1β release, and alleviated oxidative stress. Additionally, mitochondrial structure was restored by reversing fission and promoting fusion, while calcium-handling proteins (NCX-1, RYR2, and SERCA2a) were regulated to prevent intracellular calcium overload, reducing AF susceptibility.</div></div><div><h3>Conclusion</h3><div>GTS-21 mitigated atrial inflammation and reduced the incidence of AF in mice with sepsis by regulating macrophage polarization, reducing oxidative stress, and preserving mitochondrial and calcium dynamics in cardiomyocytes. These findings highlight the therapeutic potential of GTS-21 in treating sepsis-induced AF.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"154 ","pages":"Article 114561"},"PeriodicalIF":4.8,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143777495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}