Department of Molecular & Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
Department of Infectious Diseases, Hunan Key Laboratory of Viral Hepatitis, Xiangya Hospital, Central South University, Changsha, China.
Nat Commun. 2022 Aug 30;13(1):5111. doi: 10.1038/s41467-022-32575-8.
Excessive cholangiocyte expansion (ductular reaction) promotes liver disease progression, but the underlying mechanism is poorly understood. Here we identify biliary NF-κB-inducing kinase (NIK) as a pivotal regulator of ductular reaction. NIK is known to activate the noncanonical IKKα/NF-κB2 pathway and regulate lymphoid tissue development. We find that cholangiocyte NIK is upregulated in mice with cholestasis induced by bile duct ligation (BDL), 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), or α-naphtyl-isothiocyanate (ANIT). DDC, ANIT, or BDL induces ductular reaction, liver injury, inflammation, and fibrosis in mice. Cholangiocyte-specific deletion of NIK, but not IKKα, blunts these pathological alterations. NIK inhibitor treatment similarly ameliorates DDC-induced ductular reaction, liver injury, and fibrosis. Biliary NIK directly increases cholangiocyte proliferation while suppressing cholangiocyte death, and it also promotes secretion of cholangiokines from cholangiocytes. Cholangiokines stimulate liver macrophages and hepatic stellate cells, augmenting liver inflammation and fibrosis. These results unveil a NIK/ductular reaction axis and a NIK/cholangiokine axis that promote liver disease progression.
过量的胆管细胞扩张（胆管反应）促进肝病进展，但其中的机制尚不清楚。在这里，我们发现胆 NF-κB 诱导激酶 (NIK) 是胆管反应的关键调节因子。已知 NIK 可激活非经典 IKKα/NF-κB2 途径并调节淋巴组织发育。我们发现，在胆管结扎 (BDL)、5-二乙氧羰基-1,4-二氢可待因 (DDC) 或α-萘基异硫氰酸酯 (ANIT) 诱导的胆汁淤积小鼠中，胆管细胞 NIK 上调。DDC、ANIT 或 BDL 可诱导小鼠发生胆管反应、肝损伤、炎症和纤维化。胆管细胞特异性 NIK 缺失，但不是 IKKα 缺失，可减轻这些病理改变。NIK 抑制剂治疗同样可改善 DDC 诱导的胆管反应、肝损伤和纤维化。胆管 NIK 直接增加胆管细胞增殖，同时抑制胆管细胞死亡，并促进胆管细胞分泌胆肠激素。胆肠激素刺激肝巨噬细胞和肝星状细胞，加剧肝炎症和纤维化。这些结果揭示了 NIK/胆管反应轴和 NIK/胆肠激素轴促进肝病进展。
