Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells.

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

doi:10.3389/fcell.2020.00601

Cong Wang, Wenshu Zhang + Show 10 more

Open Access

https://doi.org/10.3389/fcell.2020.00601

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Abstract

It is a well-documented event that fibroblast growth factors (FGFs) regulate liver development and homeostasis in autocrine, paracrine, and endocrine manners via binding and activating FGF receptors (FGFRs) tyrosine kinase in hepatocytes. Recent research reveals that hepatic stellate cells (HSCs) play a fundamental role in liver immunology. However, how FGF signaling in HSCs regulates liver inflammation remains unclear. Here, we report that FGF promoted NF-κB signaling, an inflammatory pathway, in human HSCs, which was associated with FGFR1 expression. Both FGF and NF-κB signaling in HSCs were compromised by FGFR1 tyrosine kinase inhibitor. After stimulating HSCs with proinflammatory cytokines, expression of multiple FGF ligands was significantly increased. However, disruption of FGF signaling with FGFR inhibitors prominently reduced the apoptosis, inflammatory response, NF-κB nuclear translocation, and expression of matrix metalloproteinase-9 (MMP-9) induced by TNFα in HSCs. Interestingly, FGF21 significantly alleviated the inflammation responses in the concanavalin A (Con A)-induced acutely injured liver. Unlike canonic FGFs that elicit signals through activating the FGFR–heparan sulfate complex, FGF21 activates the FGFR–KLB complex and elicits a different set of signals. Therefore, the finding here indicates the urgency of developing pathway-specific inhibitors that only suppress canonical FGF, but not non-canonical FGF21, signaling for alleviating inflammation in the liver, which is presented in all stages of diseased liver.

Highlights

Inflammatory reactions drive multiple cellular processes in the chronically diseased liver, in liver fibrosis that is a highly conserved response to hepatic injury (Pradhan-Sundd et al, 2018)
Treating LX-2 cells with FGF1 induced strong phosphorylation of FRS2α and ERK1/2, as well as IKKα, IKKβ, IκBα, and p65, in LX-2 cells at a time-dependent manner (Figure 1B). These results indicate the association between the Fibroblast growth factor (FGF) receptors (FGFRs) and NF-κB signal pathways, which is consistent with our previous report (Wang et al, 2018)
We showed that inhibition of FGFR compromised TNFα-induced activation of the NF-κB pathway in hepatic stellate cells (HSCs) and suppresses the inflammation induced by acute liver injuries

Summary

Introduction

Inflammatory reactions drive multiple cellular processes in the chronically diseased liver, in liver fibrosis that is a highly conserved response to hepatic injury (Pradhan-Sundd et al, 2018). It occurs in patients with many kinds of liver diseases, such as chronic viral hepatitis, non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease (ALD), and cholestatic and autoimmune liver disease. The distinct characteristic feature in the process of liver fibrosis is the transformation of hepatic stellate cells (HSCs) from quiescent and lipid-storing cells to activated and extracellular matrix (ECM)-producing cells (Lei et al, 2016). The links between hepatic inflammation and fibrosis have been intensively studied.

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