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comprehensive characterization of hepatocyte-derived extracellular vesicles identifies direct mirna-based regulation of hepatic stellate cells and damp-based hepatic macrophage il-1β and il-17 upregulation in alcoholic hepatitis mice
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نویسنده
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eguchi akiko ,yan rui ,pan stephanie q ,wu raymond ,kim jihoon ,chen yibu ,ansong charles ,smith richard d. ,tempaku mina ,ohno-machado lucila ,takei yoshiyuki ,feldstein ariel e. ,tsukamoto hidekazu
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منبع
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journal of molecular medicine - 2020 - دوره : 98 - شماره : 7 - صفحه:1021 -1034
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چکیده
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Extracellular vesicles (evs) have been growingly recognized as biomarkers and mediators of alcoholic liver disease (ald) in human and mice. here we characterized hepatocyte-derived evs (hc-evs) and their cargo for their biological functions in a novel murine model that closely resembles liver pathology observed in patients with alcoholic hepatitis (ah), the most severe spectrum of ald. the numbers of circulating evs and hc-evs were significantly increased by 10-fold in ah mice compared with control mice. the mirna (mir)–seq analysis detected 20 upregulated and 4 downregulated mirnas (p < 0.001–0.05) in ah-hc-evs. treatment of murine primary hepatic stellate cells (hscs) with ah-hc-evs induced α-sma (p < 0.05) and col1a1 (p < 0.001). smad7 and nr1d2 genes, which were downregulated in hscs from the ah mice, were predicted targets of 20 mirs upregulated in ah-hc-evs. among them were mir-27a and mir-181 which upon transfection in hscs, indeed repressed nr1d2, the quiescent hsc marker. ah-hc-evs were also enriched with organelle proteins and mitochondrial dna (10-fold, p < 0.05) and upregulated il-1β and il-17 production by hepatic macrophages (hms) from ah mice in a tlr9-dependent manner. these results demonstrate hc-ev release is intensified in ah and suggest that ah-hc-evs orchestrate liver fibrogenesis by directly targeting the quiescent hsc transcripts via a unique set of mirnas and by amplifying hsc activation via damp-based induction of profibrogenic il-1β and il-17 by hms. • circulating evs and hc-evs were increased in ah mice compared with control mice • ah-hc-evs were enriched in mirnas, organelle proteins, and mitochondrial dna • ah-hc-evs increased cytokine production by ah-hms in a tlr9-dependent manner
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کلیدواژه
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ah ,hepatocyte-derived evs ,mirnas ,damps ,hsc activation ,hepatic macrophage activation
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آدرس
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mie university, graduate school of medicine, department of gastroenterology and hepatology, japan. university of california san diego, department of pediatrics, usa. southern california research center for alpd and cirrhosis, usa. jst, japan, southern california research center for alpd and cirrhosis, usa. keck school of medicine of the university of southern california, department of pathology, usa, southern california research center for alpd and cirrhosis, usa. keck school of medicine of the university of southern california, department of pathology, usa, southern california research center for alpd and cirrhosis, usa. keck school of medicine of the university of southern california, department of pathology, usa, university of california san diego, department of biomedical informatics, usa, keck school of medicine of the university of southern california, usa, pacific northwest national laboratory, richland, usa, pacific northwest national laboratory, richland, usa, mie university, graduate school of medicine, department of gastroenterology and hepatology, japan, university of california san diego, department of biomedical informatics, usa, mie university, graduate school of medicine, department of gastroenterology and hepatology, japan, university of california san diego, department of pediatrics, usa. southern california research center for alpd and cirrhosis, usa, southern california research center for alpd and cirrhosis, usa. keck school of medicine of the university of southern california, department of pathology, usa. greater los angeles va healthcare system, los angeles, usa
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Authors
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