Inhibition of immunocyte infiltration and activation has been suggested to effectively ameliorate nonalcoholic steatohepatitis (NASH). Paired immunoglobulin-like receptor B (PirB) and its human ortholog receptor, leukocyte immunoglobulin-like receptor B (LILRB2), are immune-inhibitory receptors. However, their role in NASH pathogenesis is still unclear. Here, we demonstrate that PirB/LILRB2 regulates the migration of macrophages during NASH by binding with its ligand angiopoietin-like protein 8 (ANGPTL8). Hepatocyte-specific ANGPTL8 knockout reduces MDM infiltration and resolves lipid accumulation and fibrosis progression in the livers of NASH mice. In addition, PirB−/− bone marrow (BM) chimeras abrogate ANGPTL8-induced MDM migration to the liver. And yet, PirB ectodomain protein could ameliorate NASH by sequestering ANGPTL8. Furthermore, LILRB2-ANGPTL8 binding-promoted MDM migration and inflammatory activation are also observed in human peripheral blood monocytes. Taken together, our findings reveal the role of PirB/LILRB2 in NASH pathogenesis and identify PirB/LILRB2-ANGPTL8 signaling as a potential target for the management or treatment of NASH.

Inhibition of immunocyte infiltration and activation has been proven to effectively ameliorate hepatic inflammation and fibrosis in nonalcoholic steatohepatitis (NASH). Paired immunoglobulin-like receptor B (PirB) and its human orthologue receptor, leukocyte immunoglobulin-like receptor B (LILRB2), are immune-inhibitory receptors with unknown roles in NASH. Here, we demonstrate that PirB/LILRB2 regulates the migration of macrophages in NASH pathogenesis and fibrogenesis by binding to its NASH-associated ligand angiopoietin-like protein 8 (ANGPTL8). Mechanistically, PirB facilitates the ANGPTL8-induced infiltration of monocyte-derived macrophages (MDMs) into the liver by regulating the phosphorylation of P38, AKT, and P65. Hepatocyte-specific knockout of its ligand ANGPTL8 reduces MDM infiltration and resolves lipid accumulation and fibrosis progression in the livers of NASH mice. In addition, PirB−/− bone marrow (BM) chimaeras abrogated ANGPTL8-induced MDM migration to the liver. PirB ectodomain protein can ameliorate the lipid accumulation inflammatory response and fibrosis of NASH by sequestering ANGPTL8. Furthermore, LILRB2-ANGPTL8-axis-associated MDM migration and inflammatory activation are also observed in human peripheral blood monocytes. Taken together, our findings reveal a novel role of PirB/LILRB2 in NASH pathogenesis and identify PirB/LILRB2-ANGPTL8 signalling as a potential target for the management or treatment of NASH.