Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells
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) pl...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2020-07-01
|
| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fcell.2020.00601/full |
| _version_ | 1819065025036288000 |
|---|---|
| author | Cong Wang Yuelong Li Hao Li Yali Zhang Zhangguo Ying Xuye Wang Tingting Zhang Wenshu Zhang Zhichao Fan Xiaokun Li Jisheng Ma Xuebo Pan |
| author_facet | Cong Wang Yuelong Li Hao Li Yali Zhang Zhangguo Ying Xuye Wang Tingting Zhang Wenshu Zhang Zhichao Fan Xiaokun Li Jisheng Ma Xuebo Pan |
| author_sort | Cong Wang |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T15:39:54Z |
| format | Article |
| id | doaj.art-ad927944bfd84694910a4c50637ee2c9 |
| institution | Directory Open Access Journal |
| issn | 2296-634X |
| language | English |
| last_indexed | 2024-12-21T15:39:54Z |
| publishDate | 2020-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cell and Developmental Biology |
| spelling | doaj.art-ad927944bfd84694910a4c50637ee2c92022-12-21T18:58:32ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-07-01810.3389/fcell.2020.00601529126Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate CellsCong WangYuelong LiHao LiYali ZhangZhangguo YingXuye WangTingting ZhangWenshu ZhangZhichao FanXiaokun LiJisheng MaXuebo PanIt 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.https://www.frontiersin.org/article/10.3389/fcell.2020.00601/fullFGFRMMP9hepatic stellate cellinflammationNF-κB |
| spellingShingle | Cong Wang Yuelong Li Hao Li Yali Zhang Zhangguo Ying Xuye Wang Tingting Zhang Wenshu Zhang Zhichao Fan Xiaokun Li Jisheng Ma Xuebo Pan Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells Frontiers in Cell and Developmental Biology FGFR MMP9 hepatic stellate cell inflammation NF-κB |
| title | Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells |
| title_full | Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells |
| title_fullStr | Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells |
| title_full_unstemmed | Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells |
| title_short | Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells |
| title_sort | disruption of fgf signaling ameliorates inflammatory response in hepatic stellate cells |
| topic | FGFR MMP9 hepatic stellate cell inflammation NF-κB |
| url | https://www.frontiersin.org/article/10.3389/fcell.2020.00601/full |
| work_keys_str_mv | AT congwang disruptionoffgfsignalingamelioratesinflammatoryresponseinhepaticstellatecells AT yuelongli disruptionoffgfsignalingamelioratesinflammatoryresponseinhepaticstellatecells AT haoli disruptionoffgfsignalingamelioratesinflammatoryresponseinhepaticstellatecells AT yalizhang disruptionoffgfsignalingamelioratesinflammatoryresponseinhepaticstellatecells AT zhangguoying disruptionoffgfsignalingamelioratesinflammatoryresponseinhepaticstellatecells AT xuyewang disruptionoffgfsignalingamelioratesinflammatoryresponseinhepaticstellatecells AT tingtingzhang disruptionoffgfsignalingamelioratesinflammatoryresponseinhepaticstellatecells AT wenshuzhang disruptionoffgfsignalingamelioratesinflammatoryresponseinhepaticstellatecells AT zhichaofan disruptionoffgfsignalingamelioratesinflammatoryresponseinhepaticstellatecells AT xiaokunli disruptionoffgfsignalingamelioratesinflammatoryresponseinhepaticstellatecells AT jishengma disruptionoffgfsignalingamelioratesinflammatoryresponseinhepaticstellatecells AT xuebopan disruptionoffgfsignalingamelioratesinflammatoryresponseinhepaticstellatecells |