BMDM-derived ORP8 suppresses lipotoxicity and inflammation by relieving endoplasmic reticulum stress in mice with
Yi Chen1,2, Kangjie Xie3, Caiyang Chen1,2
1Department of Anesthesiology, Renji Hospital, Jiaotong University School of Medicine, No. 160, Pujian Road, Pudong New District, Shanghai, 200217, China.
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.
Insights
Anti-inflammatory macrophage-derived extracellular vesicles (EVs) show therapeutic potential for metabolic dysfunction-associated steatohepatitis (MASH). These EVs, containing Osbpl8, reduce liver inflammation and lipotoxicity by modulating ER stress, offering a novel treatment strategy for MASH.
Area of Science:
- Hepatology and Immunology
- Cellular and Molecular Biology
Background:
- Metabolic dysfunction-associated steatohepatitis (MASH) is a prevalent liver disease with limited treatment options.
- Hepatic inflammation is a critical driver in the progression of MASH.
- Anti-inflammatory macrophages play a role in maintaining immune homeostasis.
Purpose of the Study:
- To elucidate the role of anti-inflammatory macrophages in MASH.
- To investigate the underlying molecular mechanisms by which these macrophages influence MASH progression.
Main Methods:
- Isolation and characterization of extracellular vesicles (EVs) from anti-inflammatory bone marrow-derived macrophages (BMDMs).
- In vitro studies using palmitic acid-stimulated hepatocytes treated with EVs or Osbpl8 shRNA.
- In vivo MASH model in C57BL/6 mice treated with EVs or shRNA-encoding AAV.
Main Results:
- EVs from anti-inflammatory BMDMs inhibited inflammatory responses and alleviated lipotoxicity in MASH models.
- Osbpl8 was identified as a key component in these EVs, remodeling lipid metabolism by reducing ER stress.
- Osbpl8-enriched EVs demonstrated anti-inflammatory and anti-lipotoxic effects, suggesting therapeutic potential.
Conclusions:
- Osbpl8 within EVs secreted by anti-inflammatory BMDMs is crucial for intercellular communication in MASH.
- This study reveals a novel mechanism for macrophage homeostasis regulation in MASH.
- Osbpl8-enriched EVs represent a promising therapeutic target for MASH treatment.
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