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

Abstract

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 SIRPα 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-SIRPα. 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-SIRPα, 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-SIRPα treatment avoided the adverse effect of anemia found in anti-CD47–treated mice. These findings provide evidence that impaired clearance of necHCs by liver macrophages due to CD47-SIRPα up-regulation contributes to fibrotic NASH, and suggest therapeutic blockade of the CD47-SIRPα axis as a strategy to decrease the accumulation of necHCs in NASH liver and dampen the progression of hepatic fibrosis.

Erythrocytes of Nonalcoholic Steatohepatitis Patients Contain Decreased Arginase-1 and Thrombospondin-1, and Increased Phosphatidylethanolamine Levels

“…(figure 6). Overall, we suggest that erythrocyte dysfunction is a substantial aspect of metabolic inflammation as already evidenced by previous studies [6,8,23,32] Our results explain the reported anemia in animal models of NASH, where CD47 targeting had a therapeutic potential on NASH [33,34]; since erythrocytes of NASH patients and animal models exhibit reduced CD47 levels and increased pro-phagocytic signals, targeting of CD47 on erythrocytes enhances their phagocytosis. In addition, our results could also explain the negative impact of the chronic CD47 targeting in NASH animal models [35]; erythrophagocytosis would lead to hepatic dysfunction.…”

The potential protective effect of liraglutide on valproic acid induced liver injury in rats: Targeting HMGB1/RAGE axis and RIPK3/MLKL mediated necroptosis

“…39 Actually, necroptosis has been shown to have a role in the pathogenesis of a number of liver diseases, including alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and toxic hepatitis. [40][41][42] Well in line, it is proved that VPA treatment increases RIPK1 expressions and increases RIPK3 and MLKL levels and enhancing their mRNA gene expression in liver. Excessive ROS production is an imminent driving force for the execution of necroptosis owing to forming more necrosome.…”

“…Actually, necroptosis has been shown to have a role in the pathogenesis of a number of liver diseases, including alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and toxic hepatitis 40–42 …”

The diverse roles of macrophages in metabolic inflammation and its resolution

“…At the same time, liver macrophages increase their expression of the CD47 receptor, SIRPα, leading to impaired clearance of these necroptotic hepatocytes. This was reversed using anti-CD47 or anti-SIRPα treatment in mouse models of NASH, which increased the uptake of these necroptotic hepatocytes by liver macrophages ( Shi et al, 2022 ).…”