Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function
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Curated by eLife
eLife assessment
As shown by the authors, the focal adhesion protein, kindlin-2, plays an essential role in liver development in that its genetic inactivation leads to severe fibrosis and death in young mice. This lethality is attributed to increased liver inflammation and cell death. This work will be of interest to readers studying mechanisms of liver development and pathological fibrosis.
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Abstract
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.
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eLife assessment
As shown by the authors, the focal adhesion protein, kindlin-2, plays an essential role in liver development in that its genetic inactivation leads to severe fibrosis and death in young mice. This lethality is attributed to increased liver inflammation and cell death. This work will be of interest to readers studying mechanisms of liver development and pathological fibrosis.
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Reviewer #1 (Public Review):
Gao et al developed various genetic permutations of mouse models of kindlin-2 deficiency in the hepatocytes to explore its function. Hepatocyte-specific loss of kindlin-2 results in severe inflammatory liver injury, accelerated fibrosis/portal hypertension, and massive hepatocyte cell death by apoptosis. These effects are reversed by ablation of TNF signally or by caspase 8 deletion. AAV-mediated replacement of kindlin-2 protects the mice from chemically induced acute liver injury.
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Reviewer #2 (Public Review):
As shown in this study, the focal adhesion protein, kindlin-2, plays an essential role in liver function in that its genetic inactivation leads to severe liver fibrosis and death in young mice. This lethality is attributed to activation of TNF-mediated inflammation and caspase-8-dependent cell death since effects of kindlin-2 (Fermt2 gene) knockout can be reversed by genetic inactivation of TNF or caspase signaling. Evidence is also presented that kindlin-2 overexpression can have a mildly protective effect on acute liver toxicity. Overall, this work successfully connects kindlin-2 with normal liver function and raises the possibility that modulation of kindlin-2 could have therapeutic potential for treating liver disease.
On the other hand, the underlying mechanism explaining why kindlin-2 loss stimulates …
Reviewer #2 (Public Review):
As shown in this study, the focal adhesion protein, kindlin-2, plays an essential role in liver function in that its genetic inactivation leads to severe liver fibrosis and death in young mice. This lethality is attributed to activation of TNF-mediated inflammation and caspase-8-dependent cell death since effects of kindlin-2 (Fermt2 gene) knockout can be reversed by genetic inactivation of TNF or caspase signaling. Evidence is also presented that kindlin-2 overexpression can have a mildly protective effect on acute liver toxicity. Overall, this work successfully connects kindlin-2 with normal liver function and raises the possibility that modulation of kindlin-2 could have therapeutic potential for treating liver disease.
On the other hand, the underlying mechanism explaining why kindlin-2 loss stimulates TNF, caspase 8, inflammation, and fibrosis is not explored. As a major component of focal adhesions via its interaction with integrins, kindlin2 has primary functions in regulating cell-ECM signaling and mechanotransduction. However, this study does not connect these known functions with the liver fibrosis and inflammation observed. For example, only cursory analysis is provided concerning the effects of kindlin-2 loss on hepatocyte-ECM interactions, cytoskeletal structure, or focal adhesion distribution. Also, the slightly protective effects of Kindlin-2 overexpression on D-galactosamine/LPS-induced liver toxicity and death are not connected to the rest of the study. Also, one might question whether extending mouse survival by approx. 3-4 hrs with kindlin-2 overexpression is a potentially clinically relevant finding.
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