Mouse hepatocyte overexpression of NF‐κB‐inducing kinase (NIK) triggers fatal macrophage‐dependent liver injury and fibrosis

Year: 2014

Type: article

Abstract: UNLABELLED: Damaged, necrotic, or apoptotic hepatocytes release damage-associated molecular patterns that initiate sterile inflammation, and liver inflammation drives liver injury and fibrosis. Here we identified hepatic nuclear factor kappa B (NF-κB)-inducing kinase (NIK), a Ser/Thr kinase, as a novel trigger of fatal liver inflammation. NIK is activated by a broad spectrum of stimuli. It was up-regulated in injured livers in both mice and humans. In primary mouse hepatocytes, NIK overexpression stimulated, independently of cell injury and death, release of numerous chemokines and cytokines that activated bone marrow-derived macrophages (BMDMs). BMDMs in turn secreted proapoptotic molecules that stimulated hepatocyte apoptosis. Hepatocyte-specific expression of the NIK transgene triggered massive liver inflammation, oxidative stress, hepatocyte apoptosis, and liver fibrosis, leading to weight loss, hypoglycemia, and death. Depletion of Kupffer cells/macrophages reversed NIK-induced liver destruction and death. CONCLUSION: the hepatocyte NIK-liver immune cell axis promotes liver inflammation, injury, and fibrosis, thus driving liver disease progression.

Source: Hepatology

DOI: 10.1002/hep.27348

Authors: Hong Shen, Liang Sheng, Zheng Chen, Lin Jiang, Haoran Su, Lei Yin, M. Bishr Omary, Liangyou Rui

Institutions: University of Michigan, Michigan Medicine

Language: English

Topic: Liver physiology and pathology

Subfield: Hepatology

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: bronze

Funders: University of Michigan, National Institutes of Health, National Institute on Aging, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases

OpenAlex ID: W1575964974