AUTHOR=Wang Cong , Li Yuelong , Li Hao , Zhang Yali , Ying Zhangguo , Wang Xuye , Zhang Tingting , Zhang Wenshu , Fan Zhichao , Li Xiaokun , Ma Jisheng , Pan Xuebo 

TITLE=Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=Volume 8 - 2020

YEAR=2020

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.00601

DOI=10.3389/fcell.2020.00601

ISSN=2296-634X

ABSTRACT=Fibroblast growth factors (FGFs) binding with fibroblast growth factor receptors (FGFRs) is a well-documented event that regulates liver development and homeostasis in autocrine, paracrine, and endocrine manners. Recent research reveals that hepatic stellate cell (HSC) plays a fundamental role of in liver immunology. However, how FGF signaling in HSCs to regulating liver inflammation remains unclear. Here we report that FGF promoted NF-κB signaling in human HSCs, which was associated with FGFR1 expression. Both FGF and NF-κB signaling in HSCs were compromised by a tyrosine kinase inhibitor of FGFR1. After stimulating HSCs with pro-inflammatory cytokine, the expression of multiple FGF ligands was significantly increased. Moreover, disruption of FGF signaling with FGFR inhibitors reduced the DNA trap, an inflammatory response, NF-κB nuclear translocation induced by TNFα, and reduced expression of matrix metalloproteinase-9 (MMP-9). Interestingly, FGF21 significantly alleviated the inflammation responses in the concanavalin A (Con A) induced acute injured liver. It is well documented that, unlike canonic FGFs that elicit signals through FGFR-heparan sulfate complex, FGF21 elicits different signaling through activating the FGFR-KLB complex. Therefore, the finding here indicates the urgency to develop pathway-specific inhibitors that only suppress canonical FGF, but not FGF21, signaling for suppressing inflammation in the liver, which is presented in all stages of diseased liver.