Division of Endocrinology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Branch of National Clinical Research Center for Metabolic Diseases, Hubei, China.
Nat Commun. 2023 Jul 22;14(1):4436. 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.
抑制免疫细胞浸润和激活已被证明能有效改善非酒精性脂肪性肝炎（NASH）。配对免疫球蛋白样受体 B（PirB）及其人类同源受体白细胞免疫球蛋白样受体 B（LILRB2）是免疫抑制受体。然而，它们在 NASH 发病机制中的作用尚不清楚。在这里，我们证明 PirB/LILRB2 通过与配体血管生成素样蛋白 8（ANGPTL8）结合来调节 NASH 期间巨噬细胞的迁移。肝细胞特异性 ANGPTL8 敲除可减少 NASH 小鼠肝脏中 MDM 的浸润，并解决脂质积累和纤维化进展。此外，PirB 骨髓（BM）嵌合体可消除 ANGPTL8 诱导的 MDM 向肝脏的迁移。然而，PirB 胞外结构域蛋白可以通过隔离 ANGPTL8 来改善 NASH。此外，还观察到 LILRB2-ANGPTL8 结合促进了人外周血单核细胞中 MDM 的迁移和炎症激活。总之，我们的研究结果揭示了 PirB/LILRB2 在 NASH 发病机制中的作用，并确定了 PirB/LILRB2-ANGPTL8 信号通路作为 NASH 管理或治疗的潜在靶点。
