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Kindlin-2 inhibits TNF/NF-κB-Caspase 8 pathway in hepatocytes to maintain liver development and function

Huanqing Gao1, Yiming Zhong1, Liang Zhou2

  • 1Department of Biochemistry, School of Medicine, Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research, Shenzhen Key Laboratory of Cell Microenvironment, Southern University of Science and Technology, Shenzhen, China.

Elife
|January 9, 2023
PubMed

Insights

Loss of Kindlin-2 protein in liver cells causes severe inflammation and liver failure by activating the tumor necrosis factor (TNF) pathway. Restoring Kindlin-2 function protects against liver injury and death.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Immunology

Background:

  • Inflammatory liver diseases contribute significantly to global morbidity and mortality.
  • The precise molecular mechanisms driving these conditions remain incompletely understood.

Purpose of the Study:

  • To investigate the role of the focal adhesion protein Kindlin-2 in maintaining liver homeostasis.
  • To elucidate the mechanisms by which Kindlin-2 influences liver inflammation and injury.

Main Methods:

  • Utilized Alb-Cre transgenic mice to specifically delete Kindlin-2 in hepatocytes.
  • Analyzed liver pathology, apoptosis, cell proliferation, and extracellular matrix accumulation.
  • Investigated the activation of the tumor necrosis factor (TNF) signaling pathway.
  • Employed genetic deletion of TNF receptor and Caspase 8 to assess pathway involvement.
  • Used adeno-associated virus (AAV) mediated gene delivery to overexpress Kindlin-2 in vivo.

Main Results:

  • Hepatocyte-specific Kindlin-2 deletion induced severe liver inflammation, apoptosis, compensatory proliferation, and massive liver fibrosis, leading to premature death.
  • Kindlin-2 deficiency resulted in abnormal activation of the TNF signaling pathway.
  • Deletion of TNF receptor or Caspase 8 in hepatocytes rescued liver function and prevented mortality.
  • Overexpression of Kindlin-2 using AAV attenuated D-galactosamine and lipopolysaccharide-induced liver injury.

Conclusions:

  • Kindlin-2 acts as a critical intrinsic inhibitor of the TNF pathway in hepatocytes.
  • Maintaining Kindlin-2 expression is essential for liver homeostasis.
  • Kindlin-2 represents a potential therapeutic target for inflammatory liver diseases.
Keywords:
TNFR/NF-kBcell biologydevelopmental biologyhepatocyteliver failuremouse

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