LILRB2/PirB mediates macrophage recruitment in fibrogenesis of nonalcoholic steatohepatitis

• Published in: Nature communications Vol. 14; no. 1; p. 4436
• Main Authors: Li, Dan-Pei, Huang, Li, Kan, Ran-Ran, Meng, Xiao-Yu, Wang, Shu-Yun, Zou, Hua-Jie, Guo, Ya-Ming, Luo, Pei-Qiong, Pan, Li-Meng, Xiang, Yu-Xi, Mao, Bei-Bei, Xie, Yu-Yu, Wang, Zhi-Han, Yang, Min, He, Rui, Yang, Yan, Liu, Zhe-Long, Xie, Jun-Hui, Ma, De-Lin, Zhang, Ben-Ping, Shao, Shi-Ying, Chen, Xi, Xu, Si-Miao, He, Wen-Tao, Li, Wen-Jun, Chen, Yong, Yu, Xue-Feng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 22.07.2023; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/127/98; 692/420/256/2515; Angiopoietin; Angiopoietin-Like Protein 8; Animals; Binding; Bone marrow; Chimeras; Fatty liver; Fibrosis; Humanities and Social Sciences; Humans; Immunoglobulins; Infiltration; Inflammation; Leukocyte migration; Lipids; Macrophages; Membrane Glycoproteins; Mice; Monocytes; multidisciplinary; Non-alcoholic Fatty Liver Disease; Pathogenesis; Peptide Hormones; Peripheral blood; Proteins; Receptors; Receptors, Immunologic - genetics; Science; Science (multidisciplinary); Sequestering
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-40183-3

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 suggested to ameliorate hepatic inflammation and fibrosis in nonalcoholic steatohepatitis. Here, the authors show PirB/LILRB2 regulates the migration of macrophages during NASH by binding with ANGPTL8, which is involved in the regulation of NASH development.