Wenxuan Lang , Chongji Wang , Jiahui Wen , Miaoqi Chen , Decheng Wei , Yanzong Jiang , Xue Li , Pengsheng Wei , Ge Jin , Qiwen Zhu
{"title":"靶向NEK7调节焦亡和肠道微生物群以减轻大鼠的抑郁样行为","authors":"Wenxuan Lang , Chongji Wang , Jiahui Wen , Miaoqi Chen , Decheng Wei , Yanzong Jiang , Xue Li , Pengsheng Wei , Ge Jin , Qiwen Zhu","doi":"10.1016/j.intimp.2025.115148","DOIUrl":null,"url":null,"abstract":"<div><div>NIMA-associated kinase 7 (NEK7) is a serine/threonine kinase that regulates the aberrant activation of the inflammasome of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), which leads to inflammatory diseases. Depression, a prevalent psychiatric condition, has been linked to neuroinflammatory processes. However, the precise molecular and cellular mechanisms underlying the role of NEK7 in depression pathogenesis remain incompletely characterized. Our study demonstrated elevated NEK7 expression in the hippocampus of maternal separation (MS) and chronic unpredictable mild stress (CUMS)-induced depressed rats. Adeno-associated virus (AAV)-mediated delivery of shNEK7 effectively alleviated depression-like behavioral deficits, downregulated pyroptosis marker protein expression, reduced inflammatory cytokine levels (interleukin-1β and interleukin-18), and preserved neuronal survival and cellular structure. Furthermore, hippocampal NEK7 knockdown restored gut microbiota homeostasis in depression-like rats, particularly affecting the relative abundance of <em>Corynebacterium</em> and <em>Prevotella</em> genera. Notably, for the first time, the metabolite corynoxine was found to be associated with hippocampal NEK7 knockdown in depression-like rats. Taken together, our results reveal that NEK7 may be a promising target for the treatment of depression and provide new experimental evidence for clinical application.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"162 ","pages":"Article 115148"},"PeriodicalIF":4.7000,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Targeting NEK7 modulates pyroptosis and gut microbiota to alleviate depression-like behavior in rats\",\"authors\":\"Wenxuan Lang , Chongji Wang , Jiahui Wen , Miaoqi Chen , Decheng Wei , Yanzong Jiang , Xue Li , Pengsheng Wei , Ge Jin , Qiwen Zhu\",\"doi\":\"10.1016/j.intimp.2025.115148\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>NIMA-associated kinase 7 (NEK7) is a serine/threonine kinase that regulates the aberrant activation of the inflammasome of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), which leads to inflammatory diseases. Depression, a prevalent psychiatric condition, has been linked to neuroinflammatory processes. However, the precise molecular and cellular mechanisms underlying the role of NEK7 in depression pathogenesis remain incompletely characterized. Our study demonstrated elevated NEK7 expression in the hippocampus of maternal separation (MS) and chronic unpredictable mild stress (CUMS)-induced depressed rats. Adeno-associated virus (AAV)-mediated delivery of shNEK7 effectively alleviated depression-like behavioral deficits, downregulated pyroptosis marker protein expression, reduced inflammatory cytokine levels (interleukin-1β and interleukin-18), and preserved neuronal survival and cellular structure. Furthermore, hippocampal NEK7 knockdown restored gut microbiota homeostasis in depression-like rats, particularly affecting the relative abundance of <em>Corynebacterium</em> and <em>Prevotella</em> genera. Notably, for the first time, the metabolite corynoxine was found to be associated with hippocampal NEK7 knockdown in depression-like rats. Taken together, our results reveal that NEK7 may be a promising target for the treatment of depression and provide new experimental evidence for clinical application.</div></div>\",\"PeriodicalId\":13859,\"journal\":{\"name\":\"International immunopharmacology\",\"volume\":\"162 \",\"pages\":\"Article 115148\"},\"PeriodicalIF\":4.7000,\"publicationDate\":\"2025-07-02\",\"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/S1567576925011385\",\"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/S1567576925011385","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
Targeting NEK7 modulates pyroptosis and gut microbiota to alleviate depression-like behavior in rats
NIMA-associated kinase 7 (NEK7) is a serine/threonine kinase that regulates the aberrant activation of the inflammasome of NOD-like receptor thermal protein domain associated protein 3 (NLRP3), which leads to inflammatory diseases. Depression, a prevalent psychiatric condition, has been linked to neuroinflammatory processes. However, the precise molecular and cellular mechanisms underlying the role of NEK7 in depression pathogenesis remain incompletely characterized. Our study demonstrated elevated NEK7 expression in the hippocampus of maternal separation (MS) and chronic unpredictable mild stress (CUMS)-induced depressed rats. Adeno-associated virus (AAV)-mediated delivery of shNEK7 effectively alleviated depression-like behavioral deficits, downregulated pyroptosis marker protein expression, reduced inflammatory cytokine levels (interleukin-1β and interleukin-18), and preserved neuronal survival and cellular structure. Furthermore, hippocampal NEK7 knockdown restored gut microbiota homeostasis in depression-like rats, particularly affecting the relative abundance of Corynebacterium and Prevotella genera. Notably, for the first time, the metabolite corynoxine was found to be associated with hippocampal NEK7 knockdown in depression-like rats. Taken together, our results reveal that NEK7 may be a promising target for the treatment of depression and provide new experimental evidence for clinical application.
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.