Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function
Inflammatory liver diseases are a major cause of morbidity and mortality worldwide; however, underlying mechanisms are incompletely understood. Here we show that deleting the focal adhesion protein Kindlin-2 expression in hepatocytes using the Alb-Cre transgenic mice causes a severe inflammation, resulting in premature death. Kindlin-2 loss accelerates hepatocyte apoptosis with subsequent compensatory cell proliferation and accumulation of the collagenous extracellular matrix, leading to massive liver fibrosis and dysfunction. Mechanistically, Kindlin-2 loss abnormally activates the tumor necrosis factor (TNF) pathway. Blocking activation of the TNF signaling pathway by deleting TNF receptor or deletion of Caspase 8 expression in hepatocytes essentially restores liver function and prevents premature death caused by Kindlin-2 loss. Finally, of translational significance, adeno-associated virus mediated overexpression of Kindlin-2 in hepatocytes attenuates the D-galactosamine and lipopolysaccharide-induced liver injury and death in mice. Collectively, we establish that Kindlin-2 acts as a novel intrinsic inhibitor of the TNF pathway to maintain liver homeostasis and may define a useful therapeutic target for liver diseases.
All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-7 and supplementary figures.
Article and author information
National Key Research and Development Program of China (2019YFA0906004)
- Guozhi Xiao
National Natural Science Foundation of China (82230081,82250710175,82172375,81991513 and 81870532)
- Guozhi Xiao
Shenzhen Municipal Science and Technology Innovation Council (JCYJ20180302174246105)
- Huanqing Gao
Shenzhen Municipal Science and Technology Innovation Council (JCYJ20220818100617036，ZDSYS20140509142721429)
- Guozhi Xiao
Guangdong Provincial Science and Technology Innovation Council Grant (2017B030301018)
- Guozhi Xiao
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All animal experiments were approved and conducted in the specific pathogen free (SPF) Experimental Animal Center of Southern University of Science and Technology (Approval number: 20200074).
- Pramod Mistry, Yale School of Medicine, United States
- Received: July 12, 2022
- Preprint posted: July 13, 2022 (view preprint)
- Accepted: January 8, 2023
- Accepted Manuscript published: January 9, 2023 (version 1)
- Version of Record published: January 18, 2023 (version 2)
© 2023, Gao et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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