| First Author | Zhang Z | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 5111 |
| PubMed ID | 36042192 | Mgi Jnum | J:327973 |
| Mgi Id | MGI:7334271 | Doi | 10.1038/s41467-022-32575-8 |
| Citation | Zhang Z, et al. (2022) Biliary NIK promotes ductular reaction and liver injury and fibrosis in mice. Nat Commun 13(1):5111 |
| abstractText | Excessive cholangiocyte expansion (ductular reaction) promotes liver disease progression, but the underlying mechanism is poorly understood. Here we identify biliary NF-kappaB-inducing kinase (NIK) as a pivotal regulator of ductular reaction. NIK is known to activate the noncanonical IKKalpha/NF-kappaB2 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 alpha-naphtyl-isothiocyanate (ANIT). DDC, ANIT, or BDL induces ductular reaction, liver injury, inflammation, and fibrosis in mice. Cholangiocyte-specific deletion of NIK, but not IKKalpha, 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. |
