BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with MASH.

IF 6.4 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Yi Chen, Kangjie Xie, Caiyang Chen, Xihui Wang, Chenchen Ma, Zhangxiang Huang, Yingfu Jiao, Weifeng Yu
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引用次数: 0

Abstract

Background and aims: Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common chronic liver diseases worldwide, and specific treatment modalities are lacking. Accumulating evidence suggests that hepatic inflammation plays a key role in the progression from hepatic steatosis to MASH. Macrophages, especially anti-inflammatory macrophages, serve as natural immune cells that maintain homeostasis in the immune microenvironment. Here, we aimed to reveal the role of anti-inflammatory macrophages in MASH and investigate the underlying mechanism involved.

Methods & results: Extracellular vesicles (EVs) were isolated from the supernatant of anti-inflammatory bone marrow-derived macrophages (BMDMs) by ultracentrifugation, and their protein profile was characterized by liquid chromatography-tandem mass spectrometry (LC‒MS/MS) analysis. Murine hepatocytes were stimulated with palmitic acid (PA) followed by treatment with EVs or oxysterol-binding protein-related protein 8 (ORP8/Osbpl8) shRNA. C57BL/6 mice were fed a methionine- and choline-deficient (MCD) diet for 3 weeks to establish MASH. The mice were then treated with EVs or shRNA-encoding AAV. In vitro and ex vivo experiments revealed that extracellular vesicles derived from anti-inflammatory BMDMs inhibited inflammatory responses and alleviated lipotoxicity during MASH. We identified Osbpl8 as a vital component of M2-BMDMs by LC-MS/MS analysis and found that Osbpl8 remodels lipid metabolism by inhibiting excessive IRE1α-XBP1-related ER stress. Furthermore, Osbpl8-enriched M2-BMDM-EVs promoted anti-inflammatory and antilipotoxic effects and could be a novel therapeutic target for the clinical treatment of MASH.

Conclusions: Our findings indicate that Osbpl8 derived from EVs secreted by anti-inflammatory BMDMs plays important roles in intercellular communication between macrophages and hepatocytes, revealing a novel regulatory mechanism of macrophage homoeostasis in MASH.

bmdm衍生的ORP8通过缓解内质网应激来抑制脂肪毒性和炎症。
背景和目的:代谢功能障碍相关脂肪性肝炎(MASH)是世界范围内最常见的慢性肝病之一,缺乏特定的治疗方式。越来越多的证据表明,肝脏炎症在肝脂肪变性到MASH的进展中起着关键作用。巨噬细胞,尤其是抗炎巨噬细胞,是维持免疫微环境稳态的天然免疫细胞。在这里,我们旨在揭示抗炎巨噬细胞在MASH中的作用并探讨其潜在机制。方法与结果:采用超离心方法从抗炎骨髓源性巨噬细胞(bmdm)上清液中分离细胞外囊泡(EVs),并采用液相色谱-串联质谱(LC-MS /MS)分析其蛋白谱。用棕榈酸(PA)刺激小鼠肝细胞,然后用ev或氧甾醇结合蛋白相关蛋白8 (ORP8/Osbpl8) shRNA处理。C57BL/6小鼠饲喂蛋氨酸和胆碱缺乏(MCD)饲粮3周,建立MASH。然后用ev或shrna编码的AAV治疗小鼠。体外和离体实验显示,抗炎bmdm衍生的细胞外囊泡抑制了炎症反应,减轻了MASH期间的脂肪毒性。我们通过LC-MS/MS分析确定Osbpl8是m2 - bmdm的重要组成部分,并发现Osbpl8通过抑制过量的ire1 α- xbp1相关的内质网应激来重塑脂质代谢。此外,富含osbpl8的m2 - bmdm - ev可促进抗炎和抗脂毒作用,可能成为临床治疗MASH的新靶点。结论:我们的研究结果表明,抗炎bmdm分泌的EVs衍生的Osbpl8在巨噬细胞与肝细胞之间的细胞间通讯中发挥重要作用,揭示了MASH中巨噬细胞稳态调节的新机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Medicine
Molecular Medicine 医学-生化与分子生物学
CiteScore
8.60
自引率
0.00%
发文量
137
审稿时长
1 months
期刊介绍: Molecular Medicine is an open access journal that focuses on publishing recent findings related to disease pathogenesis at the molecular or physiological level. These insights can potentially contribute to the development of specific tools for disease diagnosis, treatment, or prevention. The journal considers manuscripts that present material pertinent to the genetic, molecular, or cellular underpinnings of critical physiological or disease processes. Submissions to Molecular Medicine are expected to elucidate the broader implications of the research findings for human disease and medicine in a manner that is accessible to a wide audience.
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