| First Author | Wang Y | Year | 2025 |
| Journal | FASEB J | Volume | 39 |
| Issue | 23 | Pages | e71318 |
| PubMed ID | 41348430 | Mgi Jnum | J:384816 |
| Mgi Id | MGI:8328441 | Doi | 10.1096/fj.202502014RRR |
| Citation | Wang Y, et al. (2025) Biliary NF-kappaB-Inducing Kinase Promotes Ductular Reaction, Inflammation, and Fibrosis and Impedes Liver Disease Resolution. FASEB J 39(23):e71318 |
| abstractText | NF-kappaB-inducing kinase (NIK) is selectively upregulated in cholangiocytes during chronic liver disease, but its role in disease progression is poorly understood. We here show that cholangiocyte-specific overexpression of NIK (NIK(Tg)) exacerbates liver disease progression. NIK(Tg) mice were generated using a CK19-CreERT/loxp system. NIK(Tg) and wild-type control (NIK(Con)) mice were treated with thioacetamide (TAA) or 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to induce liver disease. In a separate cohort, mice were allowed a 2-week recovery period following 4 weeks of TAA administration. NIK was also ablated in human HuCC-T1 cholangiocyte cultures (HuCC-T1(NIK-/-)), and either wild-type NIK or the NIK(G885R) mutant (defective in activating IKKalpha) was reintroduced into HuCC-T1(NIK-/-) cells. We found that NIK(Tg) mice exhibited a markedly elevated liver pathology-pronounced cholangiocyte expansion, liver inflammation, and fibrosis-upon exposure to DDC or TAA, leading to death. NIK(Tg) mice, unlike NIK(Con) controls, failed to recover after cessation of toxin exposure. Deletion of NIK in HuCC-T1(NIK-/-) cells reduced cell proliferation and survival and blunted secretion of cholangiokines that activate macrophages and hepatic stellate cells (HSCs). Re-introduction of NIK into HuCC-T1(NIK-/-) cells fully rescued these defects. In contrast, re-introduction of NIK(G885R) partially rescued the defects. Collectively, these findings indicate that biliary NIK drives ductular reaction and pathogenic cholangiokine secretion through both IKKalpha-dependent and -independent mechanisms. Furthermore, aberrant biliary NIK impedes liver injury resolution and fibrosis regression, thereby contributing to poor outcomes. |
