TY - JOUR TI - Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function AU - Gao, Huanqing AU - Zhong, Yiming AU - Zhou, Liang AU - Lin, Sixiong AU - Hou, Xiaoting AU - Ding, Zhen AU - Li, Yan AU - Yao, Qing AU - Cao, Huiling AU - Zou, Xuenong AU - Chen, Di AU - Bai, Xiaochun AU - Xiao, Guozhi A2 - Mistry, Pramod A2 - Zaidi, Mone VL - 12 PY - 2023 DA - 2023/01/09 SP - e81792 C1 - eLife 2023;12:e81792 DO - 10.7554/eLife.81792 UR - https://doi.org/10.7554/eLife.81792 AB - 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. KW - TNFR/NF-kB KW - hepatocyte KW - liver failure JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -