International immunopharmacology最新文献

{"title":"Pathological roles of NETs-platelet synergy in thrombotic diseases: From molecular mechanisms to therapeutic targeting","authors":"Jiaqi Li ,&nbsp;Yifei Geng ,&nbsp;Yun Luo ,&nbsp;Xiaobo Sun ,&nbsp;Yifei Guo ,&nbsp;Zhengqi Dong","doi":"10.1016/j.intimp.2025.114934","DOIUrl":"10.1016/j.intimp.2025.114934","url":null,"abstract":"<div><div>The formation of neutrophil extracellular traps (NETs) is a novel way for neutrophils to perform organismal protective functions essential for protecting the host against infections. Nevertheless, an increasing amount of data shows that uncontrolled or excessive formation of NETs in the body leads to inflammation and thrombosis. Many serious human diseases, such as sepsis, stroke, cancer, and autoimmune diseases, are associated with thrombosis, and inhibiting its formation is essential to prevent the development of many inflammatory and thrombotic diseases. With deeper research, it has been found that there is a complex interaction between NETs and platelets: platelets activate neutrophils to form NETs, while NET components enhance platelet aggregation and activation. This self-perpetuating vicious cycle between them mediates pathological processes such as inflammation, coagulation, and thrombosis. A deeper comprehension of the underlying molecular mechanisms between them promises to be a new target for thrombotic diseases. In this review, we concentrate on a summary of NET formation and its mechanisms of action. Providing a thorough summary of how neutrophils are activated by platelets to form NETs, how NETs cause platelet activation, and how this close interaction during inflammatory events affects the course of the disease, with the aim of providing fresh targets and ideas for thrombotic disease clinical prevention and therapy.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114934"},"PeriodicalIF":4.8,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144130986","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":"The role of natural killer T cells in sepsis-associated acute kidney injury","authors":"Cheng Li ,&nbsp;Xiaopo Gao ,&nbsp;Yuan Liu ,&nbsp;Bin Yang ,&nbsp;Hongkai Dai ,&nbsp;Hui Zhao ,&nbsp;Yongshen Li","doi":"10.1016/j.intimp.2025.114953","DOIUrl":"10.1016/j.intimp.2025.114953","url":null,"abstract":"<div><div>The condition of sepsis, defined by the misregulation of the body's defensive mechanisms against infection, culminates in the potential for catastrophic organ damage and stands as a primary driver of mortality in Intensive Care Units (ICU) settings. Among patients in a critical condition, sepsis is a predominant factor in the development of acute kidney injury (AKI), and the death rate among those with both sepsis and AKI is considerably higher, underscoring the importance of addressing this health crisis. Sepsis-associated acute kidney injury (S-AKI) is a complex process involving inflammation, microcirculatory issues, and metabolic disorders. Among these, the inflammatory response has become a focal point of interest. Bridging the innate and adaptive immunity, natural killer T (NKT) cells can be rapidly activated in sepsis, contributing to sepsis-associated injury and downstream activation of inflammatory cells through the emission of Th1 or Th2 cytokines. They also contribute to S-AKI through the TNF-α/FasL and perforin pathways. Alpha-Galactosylceramide (α-GalCer), acting as a powerful activator for type I NKT (iNKT) cells, is able to regulate the secretory profile of iNKT cells, responding to the pro-inflammatory response and immunosuppressive profiles of sepsis. This review examines the part played by NKT cells in S-AKI and whether α-Galcer could function as a significant regulator in sepsis, based on studies of regression-related mechanisms.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114953"},"PeriodicalIF":4.8,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144130987","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":"B4M3 CAR-T cell enhance antitumor activity and non-tumor toxicity in ovarian cancer","authors":"Feng Ji ,&nbsp;Jing Yu ,&nbsp;Yuxin Zhu ,&nbsp;Hao Lin ,&nbsp;Kexing Gao ,&nbsp;Mengchen Rao ,&nbsp;Yiyang Shan ,&nbsp;Sicong Liu ,&nbsp;Bo Ding ,&nbsp;Yang Shen","doi":"10.1016/j.intimp.2025.114919","DOIUrl":"10.1016/j.intimp.2025.114919","url":null,"abstract":"<div><div>Chimeric antigen receptor (CAR) T cells have demonstrated promising therapeutic outcomes in hematologic malignancies, but efficacy against most solid tumors, including ovarian cancer (OC). To address CAR-T challenges, we generated CAR-T cells (B4M3 CAR-T) targeting two tumor-associated antigens, B7H3 and MSLN, simultaneously. Immunohistochemistry and proteomics technologies, were employed to analyze the xenograft tumor tissues and key organ tissues at the end of the treatment <em>in vivo</em> assays. B4M3 CAR-T cells demonstrated rapid antitumor effects under <em>in vivo</em> stress conditions, protected against organ damage, and exhibited favorable safety and tolerability. Molecular and signaling studies indicated that B4M3 CAR-T promoted tumor cell death by activating the NF-κB and TNF signaling pathways. Furthermore, B4M3 CAR-T cells enhancing the innate immune response and altering the metabolic profile. Collectively, our study successfully developed B4M3 CAR-T cells, which exhibited significant antitumor effects in ovarian cancer and it provide a novel strategy for the immunotherapy of OC.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114919"},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144130985","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":"GDF15 suppresses abdominal aortic aneurysm by upregulating AREG expression to adjust macrophage polarization","authors":"Wanying Wu ,&nbsp;Wenjing Tang ,&nbsp;Wei Liang ,&nbsp;Qin Li ,&nbsp;Xiaoyu Qi ,&nbsp;Ran Gao ,&nbsp;Peng Zhou ,&nbsp;Gezheng Chen ,&nbsp;Jinrong Xiong ,&nbsp;Xiaoying Gu ,&nbsp;Peiwu Ding ,&nbsp;Miao Yu ,&nbsp;Chao Yang ,&nbsp;Shuang Wen","doi":"10.1016/j.intimp.2025.114899","DOIUrl":"10.1016/j.intimp.2025.114899","url":null,"abstract":"<div><h3>Objective</h3><div>Inflammation plays a key role in abdominal aortic aneurysm (AAA), with macrophages being crucial. Growth differentiation factor 15 (GDF15) is a new anti-inflammatory cytokine potentially useful in AAA diagnosis and treatment, but its role is unclear.</div></div><div><h3>Methods and results</h3><div>In mice with AAA, GDF15 expression was higher in lesioned tissues. Daily intraperitoneal injection of recombinant GDF15 (rGDF15) reduced aortic dilation, inflammation, degradation of aortic wall elastin and collagen, cellular apoptosis, and increased smooth muscle cells. GDF15 knockdown worsened AAA severity. Immunohistochemistry and immunofluorescence showed rGDF15 treatment reduced M1 macrophage polarization and enhanced M2 polarization, decreasing the M1/M2 ratio. GDF15 knockdown had the opposite effect. Additionally, Amphiregulin (AREG) expression increased with rGDF15 treatment and decreased with GDF15 knockdown. Immunofluorescence colocalization revealed lower AREG expression in M1 macrophages and higher AREG expression in M2 macrophages, suggesting that AREG may be involved in the regulation of macrophage polarization by GDF15 in AAA. Mechanistically, GDF15 upregulates AREG expression by activating the TGF-βR/SMAD2/3 signaling pathway, thereby inhibiting M1 polarization and promoting M2 polarization of macrophages.</div></div><div><h3>Conclusion</h3><div>This study demonstrates that exogenous injection of rGDF15 upregulates AREG expression and regulates macrophage polarization, thereby inhibiting AAA. GDF15 may not only serve as a diagnostic and prognostic marker for AAA but also as a potential molecular target for therapeutic intervention in AAA.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114899"},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123158","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":"CEBPD is a pivotal factor for the activation of NLRP3 inflammasome in traumatic brain injury","authors":"Jiadong Lang,&nbsp;Mingkang Li,&nbsp;Boyu Sun,&nbsp;Shiyao Feng,&nbsp;JianFei Zhao,&nbsp;Gengshui Zhao,&nbsp;Guozhu Sun","doi":"10.1016/j.intimp.2025.114930","DOIUrl":"10.1016/j.intimp.2025.114930","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a significant global health concern and a leading cause of mortality and disability worldwide. Neuroinflammation is a pivotal pathological mechanism underlying secondary brain injury following TBI. CCAAT enhancer-binding protein-delta (CEBPD), a transcription factor necessary for regulating immune and inflammatory responses, plays an important role in the progression of neuroinflammatory disorders. However, the role of CEBPD in the prognosis of TBI needs to be determined. We found that the expression of CEBPD increased significantly in TBI patients and animal models, as well as in the HT-22 neuron mechanical scratch injury model. The inhibition of CEBPD by in vivo siRNA effectively suppressed neuronal death, brain edema, and brain contusion volume and alleviated neurofunctional deficits. Knocking down CEBPD considerably inhibited the activation of the neuronal NLRP3 inflammasome, downregulated the expression of the GSDMD N-terminal fragment, and reduced the production of IL-1β and IL-18, significantly mitigating neuronal pyroptosis after TBI. Increasing CEBPD levels led to the activation of the NLRP3 inflammasome and neuronal pyroptosis in the mechanical scratch injury cell model. We also determined that the NLRP3 inflammasome activated by nigericin depended on the CEBPD pathway following TBI. Our results suggested that CEBPD may serve as a pivotal factor in promoting neuronal pyroptosis and that inhibiting CEBPD might be a promising strategy for treating TBI.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114930"},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123160","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":"Research advances of PANoptosis in gastrointestinal tumors","authors":"Lin Qi ,&nbsp;Bin Lan ,&nbsp;Zhenting Zhao ,&nbsp;Yizhao Ma ,&nbsp;Jiachun Song ,&nbsp;Qingzhe Jia ,&nbsp;Pengyue Zhao ,&nbsp;Xiaohui Du","doi":"10.1016/j.intimp.2025.114931","DOIUrl":"10.1016/j.intimp.2025.114931","url":null,"abstract":"<div><div>Gastric and colorectal cancers are acknowledged as the predominant types of gastrointestinal malignancies, significantly impacting the global cancer burden. Despite advancements in basic and clinical research on gastrointestinal cancer, the pathophysiological mechanisms and developmental processes underlying these diseases remain incompletely understood. The dysregulation of programmed cell death (PCD) has been identified as a crucial factor in the progression and metastasis of malignant tumors. The effective induction of cancer cell death continues to present a major challenge in contemporary cancer research. PANoptosis, a distinctive form of PCD integrating apoptosis, pyroptosis, and necroptosis, was introduced in 2019. Upon detecting relevant stimuli, PANoptosis sensors recruit key molecules from the three death modalities through domain-specific interactions to form a PANoptosome, which executes cell death. Recent discoveries suggest that PANoptosis plays a pivotal role in the development, progression, and drug resistance of gastrointestinal cancer. Enhancing PANoptosis will provide superior control over gastrointestinal tumors through multi-pathway crosstalk and inflammatory microenvironment modulation. This review aims to serve as a comprehensive resource for researchers by exploring the molecular foundation of PANoptosis, emphasizing its importance in gastrointestinal tumor development, and addressing current challenges as well as potential future research directions in this field.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114931"},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123156","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":"HRD1 regulates tumor-associated macrophage polarization through USP7 and promotes lung cancer development","authors":"Yezhou Xia,&nbsp;Xiaowu Tan,&nbsp;Saili Zeng,&nbsp;Yixia Jiang","doi":"10.1016/j.intimp.2025.114944","DOIUrl":"10.1016/j.intimp.2025.114944","url":null,"abstract":"<div><h3>Background</h3><div>Lung cancer exhibits high mortality and incidence rates, with tumor-associated macrophages (TAMs) serving as critical contributors to cancer progression.</div><div>This study investigates the unexplored mechanistic role of HRD1—an E3 ubiquitin ligase implicated in cancer — in orchestrating TAM polarization to affect lung cancer pathogenesis.</div></div><div><h3>Methods</h3><div>HRD1 expression in lung cancer using TCGA database and validated its impact <em>via</em> IHC. THP-1 cells and macrophages isolated from murine tumor tissues <em>via</em> magnetic bead sorting were transfected with the oe-HRD1 plasmid, followed by flow cytometry, ELISA, and RT-qPCR assays to investigate HRD1's regulatory effects on macrophage polarization and function. Co-IP was employed to investigate interactions between USP7 and HRD1/PD-L1, while Immunofluorescence elucidated underlying mechanisms.</div></div><div><h3>Results</h3><div>HRD1 was highly expressed in lung cancer and promotes tumor growth in tumor-bearing mice and proliferation in THP-1 cells. Strikingly, both <em>in vivo</em> and <em>in vitro</em> overexpression of HRD1 drove macrophage M2 polarization. Mechanistically, USP7 interacted independently with HRD1 and PD-L1, while HRD1 binding to USP7 facilitated PD-L1 ubiquitination. Furthermore, HRD1 overexpression upregulated USP7 expression, thereby enhancing M2 polarization.</div></div><div><h3>Conclusion</h3><div>HRD1 promotes lung cancer progression by regulating TAM M2 polarization <em>via</em> USP7, offering novel therapeutic targets and diagnostic perspectives for early-stage lung cancer intervention.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114944"},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123161","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":"The natural compound PEITC ameliorates imiquimod-induced psoriasis in mice by suppressing neutrophil extracellular traps formation","authors":"Mei Bai ,&nbsp;Ning An ,&nbsp;Meng Cheng ,&nbsp;Jia Qin ,&nbsp;Jie Wang ,&nbsp;Rumeng Jia ,&nbsp;Wentao Liu ,&nbsp;Jingcai Cheng ,&nbsp;Qiang Xu ,&nbsp;Xuefeng Wu","doi":"10.1016/j.intimp.2025.114939","DOIUrl":"10.1016/j.intimp.2025.114939","url":null,"abstract":"<div><div>Neutrophil extracellular traps (NETs) play a key role in the development of psoriasis, a chronic inflammatory skin condition. We demonstrate the effects and possible mechanisms of phenethyl isothiocyanate (PEITC) in inhibiting NETs and alleviating psoriasis. In response to imiquimod (IMQ), multiple symptoms including scaly plaques and associated skin inflammations were induced in mice. IMQ additionally promotes the formation of NETs and the levels of inflammatory factors. Interestingly, a natural compound PEITC exerted an intensive activity in the treatment of psoriasis. It improved lesions and ameliorated ischemic coagulation symptoms in the dorsal skin of mice. PEITC also significantly reduced the expression of inflammatory factors in mice skin with an inhibition on NETs-related molecules, such as myeloperoxidase, neutrophil elastase and citrullinated histone H3. 16S rRNA sequencing analysis demonstrated that IMQ treatment induced significant gut microbiota dysbiosis in mice, suggesting potential detrimental effects on intestinal microbial homeostasis. However, PEITC administration did not show a statistically significant ameliorative effect on this IMQ-induced microbial imbalance. <em>In vitro</em> experiments demonstrated that PEITC significantly suppressed lipopolysaccharide (LPS)-induced NET formation, suggesting that its therapeutic effects in psoriasis may be due to the inhibition of bacterially driven neutrophil activation. Therefore, we identified PAD4, an important enzyme for post-translational modification of proteins in the production of NETs, as a new potential target of PEITC. Taken together, our findings suggest that PEITC could be a novel potential therapeutic drug to relieve psoriasis <em>via</em> the inhibition of NETs both <em>in vitro</em> and <em>in vivo</em>.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114939"},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123159","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":"Network pharmacology analysis reveals that coumestrol targets ZYX to inhibit ferroptosis and alleviate acute pancreatitis","authors":"Jiatong Chen ,&nbsp;Hai Xu ,&nbsp;Lin Gao ,&nbsp;Liangkun Niu ,&nbsp;Zhiwei Huang ,&nbsp;Shenglu Liu ,&nbsp;Shiyao Huang ,&nbsp;Yingjun Chen ,&nbsp;Jing Li ,&nbsp;Peng Tan ,&nbsp;Wenguang Fu","doi":"10.1016/j.intimp.2025.114948","DOIUrl":"10.1016/j.intimp.2025.114948","url":null,"abstract":"<div><h3>Aim</h3><div>The therapeutic effect of CMS on acute pancreatitis (AP) and the mechanism of targeting Zyxin (ZYX) to regulate ferroptosis in acinar cells.</div></div><div><h3>Methods</h3><div>To assess the therapeutic effects of CMS in AP, we established caerulein-induced AP and caerulein plus LPS-induced SAP mouse models. Subsequently, weighted gene co-expression network analysis (WGCNA) and network pharmacology analysis were used to investigate the mechanism and target of CMS in the treatment of AP. Molecular docking and cell biology techniques were used to explore the molecular mechanisms by which CMS mitigated ferroptosis in AP animal and cell models.</div></div><div><h3>Results</h3><div>CMS could alleviate the pathological damage of AP and SAP, inhibit ferroptosis and reduce inflammatory response. ZYX was an important target for CMS in the treatment of AP, and CMS could specifically bind to ZYX, down-regulate ZYX expression, and reduce TGF-β/SMAD pathway activity, thereby inhibiting acinar cell ferroptosis and improving pancreatic injury in AP. And we found that ZYX overexpression counteracted the inhibitory effects of CMS on TGF-β/Smad signaling and ferroptosis processes.</div></div><div><h3>Conclusion</h3><div>These results suggested that coumestrol targeting ZYX regulated the TGF-β/SMAD pathway, inhibited ferroptosis in acinar cells, and alleviated AP. Our research provided new drugs and targets for the treatment of AP.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114948"},"PeriodicalIF":4.8,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144123967","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-29a nanoparticles improve chronic insomnia by regulating microglia activation and hippocampal neuronal cell pyroptosis through PER2/NF-κB axis","authors":"Dan Hou ,&nbsp;Yujie Hu ,&nbsp;Hongxin Li ,&nbsp;Guoshuai Yang","doi":"10.1016/j.intimp.2025.114882","DOIUrl":"10.1016/j.intimp.2025.114882","url":null,"abstract":"<div><h3>Objective</h3><div>Chronic insomnia can easily lead to clinical distress or cause mental, social, physical, educational, occupational, or other functional impairments. Considering the role of circadian rhythm in insomnia, we focused on exploring the action of miR-29a in regulating the PER2 gene in improving chronic insomnia.</div></div><div><h3>Methods</h3><div>LPS induces the expression of miRNAs targeting PER2 in HMC3 and PRM cells, which was verified by RT-qPCR. Poly-lactic-<em>co</em>-glycolic acid (PLGA) nanoparticles (NP) were used to encapsulate short hairpin (sh)-miR-29a to construct sh-miR-29a-NP. Morris water environment method was employed to establish a sleep deprivation rat model to investigate the therapeutic effects of sh-miR-29a-NP. Cell viability and levels of cell polarization factors were evaluated using CCK8 and ELISA, respectively. The Morris water maze test was applied to assess the learning and memory capabilities of the rats. Immunohistochemistry, immunofluorescence, and western blot were applied to test the expression of glial cell polarization, neuronal cell activation, apoptosis, and Period2 (PER2) /nuclear factor kappa B (NF-κB) axis proteins.</div></div><div><h3>Results</h3><div>miR-29a was significantly upregulated in LPS-induced HMC3 and PRM cells, with the most significantly altered miRNAs/PER2 interaction. In LPS-induced HMC3 and PRM cells, sh-miR-29a promoted the PER2 and CD206 expressions, and inhibited the expression of ionized calcium-binding adaptor molecule 1 (IBA-1), NF-κB, and CD86, while this effect was blocked by small interfering-PER2. Further in vivo experiments confirmed that PER2 and CD206 expression was reduced, while NF-κB, CD86, and IBA-1 expression were up-regulated in the hippocampal tissue of CSD rats. However, this effect was reversed by treatment with sh-miR-29a-NP. Treatment with sh-miR-29a-NP in CSD rats shortened the escape latency and increased the number of crossings over the original platform, while inhibited the expression of NLR Family Pyrin Domain Containing 3, caspase-1, Gasdermin D (GSDMD), and TUNEL signal in the hippocampal tissue.</div></div><div><h3>Conclusion</h3><div>The regulation of PER2/NF-κB pathway by sh-miR-29a-NP promoted M2 polarization of microglial cells and inhibited neuronal cell pyroptosis, thereby improving cognitive dysfunction in chronic insomnia.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"159 ","pages":"Article 114882"},"PeriodicalIF":4.8,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144116658","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}