GENETIC ABLATION OF PANNEXIN1 COUNTERACTS LIVER FIBROSIS IN MICE

Description

Background: liver fibrosis is the final common pathway for almost all causes of chronic liver injury. This chronic disease is characterized by excessive deposition of extracellular matrix components mainly due to transdifferentiation of quiescent hepatic stellate cell into myofibroblasts-like cells, which in turn is driven by cell death and inflammation. In the last few years, paracrine cellular signaling through pannexin1 channels has emerged as a key player in cell death and inflammation, particularly in triggering the inflammasome as well as the activation and migration of leukocytes. The current study was set up to investigate the role of pannexin1 signaling in liver fibrosis. Methods: wild-type and whole body pannexin1 knock-out mice were treated with carbon tetrachloride for 8 weeks. Evaluation of the effects of genetic pannexin1 deletion was based on a number of clinically relevant read-outs, including markers of collagen deposition, hepatic stellate cell activation, macrophage numbers, inflammasome expression and inflammatory proteins. In parallel, in order to elucidate the molecular pathways affected by pannexin1 deletion as well as to mechanistically anchor the clinical observations, whole transcriptome analysis of liver tissue was performed. Results: pannexin1 knock-out mice treated with carbon tetrachloride displayed reduced collagen content, decreased hepatic stellate cell activation, reduced expression of inflammasome components and inflammatory proteins, including interleukin1β, monocyte chemoattractant protein1, tumor necrosis factorα and its receptors. This was associated with the downregulation of genes involved in transforming growth factor beta signaling, contraction and migration of activated hepatic stellate cells and Toll-like receptor 4 signaling pathway. Conclusions: these results suggest that pannexin1 channels control hepatic fibrosis through the interference with the immune response. Consequently, pannexin1 channel inhibition may constitute a novel strategy to support currently used clinical treatments of liver fibrosis.

Periode	14 sep 2018
Evenementstitel	Young BASL summer school: liver inflammation
Evenementstype	Seminar
Locatie	Brussels, Belgium
Mate van erkenning	National