Zili He , Yitie Xu , Yu Zhang , Mengqi Jin , Yinuo Sun , Fangying Tang , Chuangqi Qiu , Abass Mashud Akinfemi Junior , Yunhao Cai , Xiaodan Xu , Xianghang Chen , Kongbin Chen , Guangheng Xiang , Jian Xiao , Jian Wang , Jing Wang , Baoyi Chen
{"title":"在脊髓损伤中,白桦酸通过AMPK-HDAC5-KLF2信号通路增强自噬,促进小胶质细胞M2极化,减轻炎症","authors":"Zili He , Yitie Xu , Yu Zhang , Mengqi Jin , Yinuo Sun , Fangying Tang , Chuangqi Qiu , Abass Mashud Akinfemi Junior , Yunhao Cai , Xiaodan Xu , Xianghang Chen , Kongbin Chen , Guangheng Xiang , Jian Xiao , Jian Wang , Jing Wang , Baoyi Chen","doi":"10.1016/j.intimp.2025.114889","DOIUrl":null,"url":null,"abstract":"<div><div>Spinal cord injury (SCI) leads to neuroinflammation and activates microglia, which are crucial contributors to neurological deficits. Betulinic acid (BA), a naturally occurring pentacyclic triterpenoid, has demonstrated effectiveness in treating inflammatory and neurological disorders. This study aims to explore the potential role and underlying mechanism of BA in modulating microglial activation and inflammation in the context of SCI. Using a mouse SCI model, we assessed motor recovery via Basso Mouse Scale (BMS) and neuronal survival via H&E/Nissl staining. Western blotting, qPCR, immunofluorescence, and flow cytometry were employed to analyze microglial polarization, autophagy, and AMPK-HDAC5-KLF2 signaling in vivo and in LPS-stimulated BV2 cells. Our findings reveal that BA significantly enhances functional recovery and reduces neuronal apoptosis following SCI. Furthermore, BA facilitates the phenotypic transition of microglia from the M1 to M2 phenotype, thereby decreasing inflammatory factors in both the SCI model and LPS-stimulated BV2 cells. BA treatment restores the disrupted autophagy flux in microglia induced by SCI or LPS, which in turn mitigates M1 polarization and inflammation. Mechanistically, BA restores autophagy flux by activating the AMPK-HDAC5-KLF2 axis, thereby shifting microglia from pro-inflammatory M1 to anti-inflammatory M2 phenotype.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"158 ","pages":"Article 114889"},"PeriodicalIF":4.7000,"publicationDate":"2025-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Betulinic acid enhances autopahgy to promote microglial M2 polarization and alleviate inflammation via AMPK-HDAC5-KLF2 signaling pathways in spinal cord injury\",\"authors\":\"Zili He , Yitie Xu , Yu Zhang , Mengqi Jin , Yinuo Sun , Fangying Tang , Chuangqi Qiu , Abass Mashud Akinfemi Junior , Yunhao Cai , Xiaodan Xu , Xianghang Chen , Kongbin Chen , Guangheng Xiang , Jian Xiao , Jian Wang , Jing Wang , Baoyi Chen\",\"doi\":\"10.1016/j.intimp.2025.114889\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Spinal cord injury (SCI) leads to neuroinflammation and activates microglia, which are crucial contributors to neurological deficits. Betulinic acid (BA), a naturally occurring pentacyclic triterpenoid, has demonstrated effectiveness in treating inflammatory and neurological disorders. This study aims to explore the potential role and underlying mechanism of BA in modulating microglial activation and inflammation in the context of SCI. Using a mouse SCI model, we assessed motor recovery via Basso Mouse Scale (BMS) and neuronal survival via H&E/Nissl staining. Western blotting, qPCR, immunofluorescence, and flow cytometry were employed to analyze microglial polarization, autophagy, and AMPK-HDAC5-KLF2 signaling in vivo and in LPS-stimulated BV2 cells. Our findings reveal that BA significantly enhances functional recovery and reduces neuronal apoptosis following SCI. Furthermore, BA facilitates the phenotypic transition of microglia from the M1 to M2 phenotype, thereby decreasing inflammatory factors in both the SCI model and LPS-stimulated BV2 cells. BA treatment restores the disrupted autophagy flux in microglia induced by SCI or LPS, which in turn mitigates M1 polarization and inflammation. Mechanistically, BA restores autophagy flux by activating the AMPK-HDAC5-KLF2 axis, thereby shifting microglia from pro-inflammatory M1 to anti-inflammatory M2 phenotype.</div></div>\",\"PeriodicalId\":13859,\"journal\":{\"name\":\"International immunopharmacology\",\"volume\":\"158 \",\"pages\":\"Article 114889\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-05-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International immunopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1567576925008793\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International immunopharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1567576925008793","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Betulinic acid enhances autopahgy to promote microglial M2 polarization and alleviate inflammation via AMPK-HDAC5-KLF2 signaling pathways in spinal cord injury
Spinal cord injury (SCI) leads to neuroinflammation and activates microglia, which are crucial contributors to neurological deficits. Betulinic acid (BA), a naturally occurring pentacyclic triterpenoid, has demonstrated effectiveness in treating inflammatory and neurological disorders. This study aims to explore the potential role and underlying mechanism of BA in modulating microglial activation and inflammation in the context of SCI. Using a mouse SCI model, we assessed motor recovery via Basso Mouse Scale (BMS) and neuronal survival via H&E/Nissl staining. Western blotting, qPCR, immunofluorescence, and flow cytometry were employed to analyze microglial polarization, autophagy, and AMPK-HDAC5-KLF2 signaling in vivo and in LPS-stimulated BV2 cells. Our findings reveal that BA significantly enhances functional recovery and reduces neuronal apoptosis following SCI. Furthermore, BA facilitates the phenotypic transition of microglia from the M1 to M2 phenotype, thereby decreasing inflammatory factors in both the SCI model and LPS-stimulated BV2 cells. BA treatment restores the disrupted autophagy flux in microglia induced by SCI or LPS, which in turn mitigates M1 polarization and inflammation. Mechanistically, BA restores autophagy flux by activating the AMPK-HDAC5-KLF2 axis, thereby shifting microglia from pro-inflammatory M1 to anti-inflammatory M2 phenotype.
期刊介绍:
International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome.
The subject material appropriate for submission includes:
• Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders.
• Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state.
• Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses.
• Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action.
• Agents that activate genes or modify transcription and translation within the immune response.
• Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active.
• Production, function and regulation of cytokines and their receptors.
• Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.