Vsig4+ resident single-Kupffer cells improve hepatic inflammation and fibrosis in NASH

Abstract

The role of macrophages in the pathogenesis of nonalcoholic steatohepatitis (NASH) is complex and unclear. Here, single-cell RNA sequencing was performed on nonparenchymal cells isolated from NASH and control mice. Two main single macrophage subsets were identi ed that exhibited a signi cant change in cell percentage when NASH occurred: resident Kupffer cells (KCs; Cluster 2) and lipidassociated macrophages (LAMs; Cluster 13). Nearly 93% of single-LAMs in Cluster 13 speci cally expressed Cx3cr1, and an increase in Cx3crl + single-LAMs was speculated to play a proin ammatory role in NASH. Nearly 82% of resident single KCs in Cluster 2 speci cally expressed Cd163, and an inhibited subgroup of Cd163 + resident single-KCs was suggested to have a protective effect in NASH. Similar to Cd163, Vsig4 was both enriched in and speci c to Cluster 2. The percentage of Vsig4 + -KCs was signi cantly decreased in NASH in vivo and in vitro. Hepatocytes and hepatic stellate cells produced less lipid droplet accumulation, proin ammatory protein (TNF-α) and pro brotic protein (α-SMA) in response to coculture with Vsig4 + -KCs than in those cocultured with lipotoxic KCs. Therefore, a subgroup of Vsig4 + resident single-KCs was shown to improve hepatic in ammation and brosis in NASH.