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

Necroptosis contributes to hepatocyte death in nonalcoholic steatohepatitis (NASH), but the fate and roles of necroptotic hepatocytes (necHCs) in NASH remain unknown. We show here that the accumulation of necHCs in human and mouse NASH liver is associated with an up-regulation of the "don't-eat-me" ligand CD47 on necHCs, but not on apoptotic hepatocytes, and an increase in the CD47 receptor SIRP alpha on liver macrophages, consistent with impaired macrophage-mediated clearance of necHCs. In vitro, necHC clearance by primary liver macrophages was enhanced by treatment with either anti-CD47 or anti-SIRP alpha. 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 alpha, 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 alpha treatment avoided the adverse effect of anemia found in antiCD47-treated mice. These findings provide evidence that impaired clearance of necHCs by liver macrophages due to CD47-SIRP alpha up-regulation contributes to fibrotic NASH, and suggest therapeutic blockade of the CD47-SIRP alpha axis as a strategy to decrease the accumulation of necHCs in NASH liver and dampen the progression of hepatic fibrosis.