LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis
Danpei Li, Li Huang, Ran-Ran Kan, Xiaoyu Meng, Shuyun Wang, Huajie Zou, Yaming Guo, Pei-Qiong Luo, Limeng Pan, Yuxi Xiang, Beibei Mao, Yu-Yu Xie, Zhihan Wang, Min Yang, Rui He, Yan Yang, Zhelong Liu, Junhui Xie, Delin Ma, Benping Zhang, Shiying Shao, Xi Chen, Simiao Xu, Wentao He, Wenjun Li, Yong Chen, Xuefeng Yu
Abstract
Abstract 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.