CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis

• DOI: 10.1126/scitranslmed.abp8309
• Publication Date: 2022-11-23T18:58:19Z
• Authors: Hongxue Shi; Xiaobo Wang; Fang Li; Brennan D. Gerlach; Arif Yurdagul; Mary P. Moore; Sharon Zeldin; Hanrui Zhang; Bishuang Cai; Ze Zheng; Luca Valenti; Ira Tabas
• Keywords: CD47; Hepatic stellate cell; Sinusoid; Kupffer cell

Necroptosis contributes to hepatocyte death in nonalcoholic steatohepatitis (NASH), but the fate and roles of necroptotic hepatocytes (necHCs) NASH remain unknown. We show here that accumulation necHCs human mouse liver is associated with an up-regulation “don’t-eat-me” ligand CD47 on necHCs, not apoptotic hepatocytes, increase receptor SIRPα macrophages, consistent impaired macrophage-mediated clearance necHCs. In vitro, necHC by primary macrophages was enhanced treatment either anti-CD47 or anti-SIRPα. a proof-of-concept model inducible necroptosis, antibody increased uptake inhibited markers hepatic stellate cell (HSC) activation, which responsible for fibrogenesis. Treatment two models diet-induced anti-CD47, anti-SIRPα, AAV8-H1-shCD47 silence decreased HSC activation fibrosis. Anti-SIRPα avoided adverse effect anemia found anti-CD47–treated mice. These findings provide evidence due CD47-SIRPα fibrotic NASH, suggest therapeutic blockade axis as strategy decrease dampen progression