Gastroenterology · 2025
Adipose Tissue Macrophages in Metabolic Dysfunction-Associated Steatohepatitis Secrete Extracellular Vesicles That Activate Liver Fibrosis in Obese Male Mice.
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Rohm Theresa V, Dos Reis Felipe Castellani Gomes, Cunha E Rocha Karina, Isaac Roi, Strayer Sean, Murphy Cairo, Bandyopadhyay Gautam, Gao Hong, Ganguly Souradipta, Nguyen Tram, Wang Jinyue, Youhanna John E, Pack David, Liu Xiao, Kim Hyun Young, Jeelani Ishtiaq, Dhar Debanjan, Kisseleva Tatiana, Ying Wei, Olefsky Jerrold M
Аннотация
BACKGROUND & AIMS: Given the need for effective interventions in metabolic dysfunction-associated steatohepatitis (MASH), understanding the role of adipose tissue macrophage (ATM)-derived small extracellular vesicles (sEVs) is important. We aimed to evaluate the contribution of MASH-ATM-sEVs to the development of liver fibrosis in obese male mice.
METHODS: Using flow cytometry and nanoparticle tracking analysis, we characterized MASH-ATMs and their secreted sEVs. We assessed the fibrogenic effects of sEVs from MASH-ATMs or anti-inflammatory macrophages on stellate cells in vitro and in mice in vivo. In addition, we isolated Dicer knockdown microRNA (miRNA)-depleted sEVs from MASH-ATMs and cotreated stellate cells with MASH-ATM-sEVs and miR-155 or miR-34a antagomirs.
RESULTS: MASH-ATMs exhibited a pro-inflammatory and lipid-associated phenotype, secreting sEVs enriched in the fibrogenic miRNAs, miR-155 and miR-34a, which also down-regulate Pparg. In vitro, MASH-ATM-sEVs induced hepatic stellate cell activation and fibrogenesis and exacerbated liver fibrosis when administered to obese mice. In addition, anti-inflammatory macrophage sEVs mitigated fibrosis both in vitro and in vivo. miRNA-free Dicer knockdown-MASH-ATM-sEVs were without effects and cotreatment with miR-155/miR-34a antagomirs blocked the effects of MASH-ATM-sEVs to induce hepatic stellate cell activation.
CONCLUSIONS: This study demonstrated the role of MASH-ATM-sEVs in promoting liver fibrosis in obesity. Identification of the fibrogenic miRs, miR-155, and miR-34a, within MASH-ATM-sEVs, highlights the mechanistic importance of extrahepatic signals in MASH. These findings showed the therapeutic potential of modulating macrophage phenotypes and their sEV cargo to ameliorate MASH.
METHODS: Using flow cytometry and nanoparticle tracking analysis, we characterized MASH-ATMs and their secreted sEVs. We assessed the fibrogenic effects of sEVs from MASH-ATMs or anti-inflammatory macrophages on stellate cells in vitro and in mice in vivo. In addition, we isolated Dicer knockdown microRNA (miRNA)-depleted sEVs from MASH-ATMs and cotreated stellate cells with MASH-ATM-sEVs and miR-155 or miR-34a antagomirs.
RESULTS: MASH-ATMs exhibited a pro-inflammatory and lipid-associated phenotype, secreting sEVs enriched in the fibrogenic miRNAs, miR-155 and miR-34a, which also down-regulate Pparg. In vitro, MASH-ATM-sEVs induced hepatic stellate cell activation and fibrogenesis and exacerbated liver fibrosis when administered to obese mice. In addition, anti-inflammatory macrophage sEVs mitigated fibrosis both in vitro and in vivo. miRNA-free Dicer knockdown-MASH-ATM-sEVs were without effects and cotreatment with miR-155/miR-34a antagomirs blocked the effects of MASH-ATM-sEVs to induce hepatic stellate cell activation.
CONCLUSIONS: This study demonstrated the role of MASH-ATM-sEVs in promoting liver fibrosis in obesity. Identification of the fibrogenic miRs, miR-155, and miR-34a, within MASH-ATM-sEVs, highlights the mechanistic importance of extrahepatic signals in MASH. These findings showed the therapeutic potential of modulating macrophage phenotypes and their sEV cargo to ameliorate MASH.