Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells

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.

Epiregulin (EREG) and Myocardin Related Transcription Factor A (MRTF-A) Form a Feedforward Loop to Drive Hepatic Stellate Cell Activation

“…Our data indicate that exposure of cultured HSCs to recombinant epiregulin accelerated the production of pro-fibrogenic genes ( Figure 3 ). This is consistent with previously reported observations that other members of the EGF family including EGF ( Lin and Chen, 2008 ), heparin-bound EGF (HB-EGF) ( Takemura et al, 2013 ), FGF ( Wang et al, 2020 ), and amphiregulin ( Perugorria et al, 2008 ) all contribute to HSC trans-differentiation and liver fibrosis. Of note, all four EGF ligands signal through the same receptor (EGFR) ( Riese and Cullum, 2014 ).…”

Expression Analysis of FGF/FGFR and FOX Family Proteins in Mucosal Tissue Obtained from Orofacial Cleft-Affected Children

“…FGFR1 has also been shown to be widely expressed in the myofibroblasts of injured palates, suggesting that FGFR1 signaling is also important for palate repair during injury [ 8 , 36 ]. Finally, it has been demonstrated that disruption of FGFR1 signaling reduces local inflammation by restraining activation of the NF-κB signaling cascades [ 37 , 38 ]. Clearly, FGFR1 plays a key role in maintaining normal development processes and in preventing fibrosis and inflammation.…”

“…It has been reported that the bFGF/FGFR1 axis can exert an anti-inflammatory response in astrocyte-mediated neuroinflammation, especially after infrasound exposure [ 54 ]. However, other authors have reported that the axis exerts a pro-inflammatory effect [ 38 , 40 , 55 ]. Hence, in the case of orofacial clefts, we postulate that this axis indeed exerts a pro-inflammatory effect.…”

A20 Attenuates Lipopolysaccharide-Induced Inflammation Through MAPK/ERK/JNK Pathway in LX-2 Cells

“…Quiescent HSCs are vitamin A-storing cells located in the perisinusoidal space near the sinusoid endothelial cells (SEC) and hepatocytes (6). Hepatic stellate cells can become activated due to chemokines and cytokines released during liver injury.…”

“…Lipopolysaccharide (LPS) can induce severe inflammation and enhance fibrosis in liver damage models (11). Treating human HSCs with LPS dramatically activates the inflammatory signaling pathway and aggravates the accumulation of proinflammatory chemokines (6). A20 is an intracellular ubiquitin-editing enzyme that has been shown as a crucial hepatoprotective factor to prevent chronic liver inflammation (12).…”