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In vitro, necHC clearance by primary liver macrophages was enhanced by treatment with either anti-CD47 or anti-SIRP\u03b1. In a proof-of-concept mouse model of inducible hepatocyte necroptosis, anti-CD47 antibody treatment increased necHC uptake by liver macrophages and inhibited markers of hepatic stellate cell (HSC) activation, which is responsible for liver fibrogenesis. Treatment of two mouse models of diet-induced NASH with anti-CD47, anti-SIRP\u03b1, or AAV8-H1-shCD47 to silence CD47 in hepatocytes increased the uptake of necHC by liver macrophages and decreased markers of HSC activation and liver fibrosis. Anti-SIRP\u03b1 treatment avoided the adverse effect of anemia found in anti-CD47\u2013treated mice. These findings provide evidence that impaired clearance of necHCs by liver macrophages due to CD47-SIRP\u03b1 up-regulation contributes to fibrotic NASH, and suggest therapeutic blockade of the CD47-SIRP\u03b1 axis as a strategy to decrease the accumulation of necHCs in NASH liver and dampen the progression of hepatic fibrosis.<\/jats:p>","DOI":"10.1126\/scitranslmed.abp8309","type":"journal-article","created":{"date-parts":[[2022,11,23]],"date-time":"2022-11-23T13:58:19Z","timestamp":1669211899000},"source":"Crossref","is-referenced-by-count":89,"title":["CD47-SIRP\u03b1 axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis"],"prefix":"10.1126","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9877-0369","authenticated-orcid":true,"given":"Hongxue","family":"Shi","sequence":"first","affiliation":[{"name":"Department of Medicine, Columbia University Irving Medical Center, New\u00a0York, NY 10032, 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