TLR4 mediates glucolipotoxicity-induced mitochondrial dysfunction in osteoblasts by enhancing NLRP3-MAVS expression and interaction

IF 4.8 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-03-17 DOI:10.1016/j.intimp.2025.114438

Ximei Shen , Xiaoyuan Chen , Shuai Zhong , Yongze Zhang , Xuan Zhou , Chao Lan , Jiebin Lin , Lifeng Zheng , Sunjie Yan

{"title":"TLR4 mediates glucolipotoxicity-induced mitochondrial dysfunction in osteoblasts by enhancing NLRP3-MAVS expression and interaction","authors":"Ximei Shen , Xiaoyuan Chen , Shuai Zhong , Yongze Zhang , Xuan Zhou , Chao Lan , Jiebin Lin , Lifeng Zheng , Sunjie Yan","doi":"10.1016/j.intimp.2025.114438","DOIUrl":null,"url":null,"abstract":"<div><div>Mitochondrial dysfunction is a critical mechanism underlying diabetic bone loss, which is driven by the inhibition of osteoblast differentiation due to glucolipotoxicity. The molecular mechanisms through which glucolipotoxicity induces mitochondrial dysfunction remain poorly understood. In this study, we observed an upregulation of Toll-like receptor 4 (TLR4) expression in osteoblasts subjected to glycolipotoxic conditions, which was associated with mitochondrial dysfunction. Proteomic analysis revealed that TLR4 plays a crucial role in glucolipotoxicity and is closely linked to mitochondrial function in osteoblasts. Knockdown of TLR4 was found to alleviate osteoblast differentiation disorders and mitochondrial dysfunction as well as mitochondria-mediated apoptosis induced by glucolipotoxicity. In contrast, overexpression of TLR4 exacerbated the detrimental effects of glucolipotoxicity. Mechanistically, glucolipotoxicity activates TLR4, resulting in increased expression of NLRP3 (NOD-like receptor protein 3) and MAVS (Mitochondrial antiviral signaling protein), which promotes the interaction between NLRP3 and MAVS. This cascade leads to increased intracellular reactive oxygen species, decreased ATP levels, elevated expression of Caspase-1, GSDMD, Bax, and reduced expression of the anti-apoptotic protein Bcl-2. Furthermore, TLR4 knockout was shown to mitigate bone loss in diabetic rats. Proteomic analysis revealed that the improvement in the expression of proteins related to mitochondrial function and osteogenic function in diabetic rats is associated with TLR4 knockout. Diabetic osteoporosis may be associated with increased TLR4 expression and disturbed oxidative phosphorylation.</div><div>In conclusion, glucolipotoxicity activates TLR4, which subsequently induces the expression and interaction of NLRP3-MAVS, leading to mitochondrial dysfunction and inhibition of osteoblast differentiation. This process contributes to bone mass loss in diabetes.</div></div>","PeriodicalId":13859,"journal":{"name":"International immunopharmacology","volume":"153 ","pages":"Article 114438"},"PeriodicalIF":4.8000,"publicationDate":"2025-03-17","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/S156757692500428X","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"IMMUNOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Mitochondrial dysfunction is a critical mechanism underlying diabetic bone loss, which is driven by the inhibition of osteoblast differentiation due to glucolipotoxicity. The molecular mechanisms through which glucolipotoxicity induces mitochondrial dysfunction remain poorly understood. In this study, we observed an upregulation of Toll-like receptor 4 (TLR4) expression in osteoblasts subjected to glycolipotoxic conditions, which was associated with mitochondrial dysfunction. Proteomic analysis revealed that TLR4 plays a crucial role in glucolipotoxicity and is closely linked to mitochondrial function in osteoblasts. Knockdown of TLR4 was found to alleviate osteoblast differentiation disorders and mitochondrial dysfunction as well as mitochondria-mediated apoptosis induced by glucolipotoxicity. In contrast, overexpression of TLR4 exacerbated the detrimental effects of glucolipotoxicity. Mechanistically, glucolipotoxicity activates TLR4, resulting in increased expression of NLRP3 (NOD-like receptor protein 3) and MAVS (Mitochondrial antiviral signaling protein), which promotes the interaction between NLRP3 and MAVS. This cascade leads to increased intracellular reactive oxygen species, decreased ATP levels, elevated expression of Caspase-1, GSDMD, Bax, and reduced expression of the anti-apoptotic protein Bcl-2. Furthermore, TLR4 knockout was shown to mitigate bone loss in diabetic rats. Proteomic analysis revealed that the improvement in the expression of proteins related to mitochondrial function and osteogenic function in diabetic rats is associated with TLR4 knockout. Diabetic osteoporosis may be associated with increased TLR4 expression and disturbed oxidative phosphorylation.

In conclusion, glucolipotoxicity activates TLR4, which subsequently induces the expression and interaction of NLRP3-MAVS, leading to mitochondrial dysfunction and inhibition of osteoblast differentiation. This process contributes to bone mass loss in diabetes.

Abstract Image

查看原文本刊更多论文

求助全文

约1分钟内获得全文求助全文

来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

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.