Biliary NIK promotes ductular reaction and liver injury and fibrosis in mice

Zhiguo Zhang, Xiao Zhong, Hong Shen, Liang Sheng, Suthat Liangpunsakul, Anna S. Lok, M. Bishr Omary, Shaomeng Wang and Liangyou Rui ()
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Zhiguo Zhang: University of Michigan Medical School
Xiao Zhong: University of Michigan Medical School
Hong Shen: University of Michigan Medical School
Liang Sheng: University of Michigan Medical School
Suthat Liangpunsakul: Indiana University School of Medicine
Anna S. Lok: University of Michigan Medical School
M. Bishr Omary: University of Michigan Medical School
Shaomeng Wang: University of Michigan Medical School
Liangyou Rui: University of Michigan Medical School

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-32575-8

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