SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic SteatohepatitisSummary
Background & Aims: Spleen tyrosine kinase (SYK) signaling pathway regulates critical processes in innate immunity, but its role in parenchymal cells remains elusive in chronic liver diseases. We investigate the relative contribution of SYK and its substrate c-Abl Src homology 3 domain-bindin...
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Elsevier
2022
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oai:doaj.org-article:7c2834e876ae418c87a2d3e981267d102021-11-14T04:34:12ZSYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic SteatohepatitisSummary2352-345X10.1016/j.jcmgh.2021.08.004https://doaj.org/article/7c2834e876ae418c87a2d3e981267d102022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001715https://doaj.org/toc/2352-345XBackground & Aims: Spleen tyrosine kinase (SYK) signaling pathway regulates critical processes in innate immunity, but its role in parenchymal cells remains elusive in chronic liver diseases. We investigate the relative contribution of SYK and its substrate c-Abl Src homology 3 domain-binding protein-2 (3BP2) in both myeloid cells and hepatocytes in the onset of metabolic steatohepatitis. Methods: Hepatic SYK-3BP2 pathway was evaluated in mouse models of metabolic-associated fatty liver diseases (MAFLD) and in obese patients with biopsy-proven MAFLD (n = 33). Its role in liver complications was evaluated in Sh3bp2 KO and myeloid-specific Syk KO mice challenged with methionine and choline deficient diet and in homozygous Sh3bp2KI/KI mice with and without SYK expression in myeloid cells. Results: Here we report that hepatic expression of 3BP2 and SYK correlated with metabolic steatohepatitis severity in mice. 3BP2 deficiency and SYK deletion in myeloid cells mediated the same protective effects on liver inflammation, injury, and fibrosis priming upon diet-induced steatohepatitis. In primary hepatocytes, the targeting of 3BP2 or SYK strongly decreased the lipopolysaccharide-mediated inflammatory mediator expression and 3BP2-regulated SYK expression. In homozygous Sh3bp2KI/KI mice, the chronic inflammation mediated by the proteasome-resistant 3BP2 mutant promoted severe hepatitis and liver fibrosis with augmented liver SYK expression. In these mice, the deletion of SYK in myeloid cells was sufficient to prevent these liver lesions. The hepatic expression of SYK is also up-regulated with metabolic steatohepatitis and correlates with liver macrophages in biopsy-proven MAFLD patients. Conclusions: Collectively, these data suggest an important role for the SYK-3BP2 pathway in the pathogenesis of chronic liver inflammatory diseases and highlight its targeting in hepatocytes and myeloid cells as a potential strategy to treat metabolic steatohepatitis.Carmelo LuciElodie VieiraManon BourinetDéborah RousseauStéphanie BonnafousStéphanie PatourauxLauren LefevreFrederic LarbretVirginie Prod’hommeAntonio IannelliAlbert TranRodolphe AntyBéatrice Bailly-MaitreMarcel DeckertPhilippe GualElsevierarticleSYK3BP2TREM1TLR4MAFLDNASHDiseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 173-191 (2022) |
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SYK 3BP2 TREM1 TLR4 MAFLD NASH Diseases of the digestive system. Gastroenterology RC799-869 |
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SYK 3BP2 TREM1 TLR4 MAFLD NASH Diseases of the digestive system. Gastroenterology RC799-869 Carmelo Luci Elodie Vieira Manon Bourinet Déborah Rousseau Stéphanie Bonnafous Stéphanie Patouraux Lauren Lefevre Frederic Larbret Virginie Prod’homme Antonio Iannelli Albert Tran Rodolphe Anty Béatrice Bailly-Maitre Marcel Deckert Philippe Gual SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic SteatohepatitisSummary |
| description |
Background & Aims: Spleen tyrosine kinase (SYK) signaling pathway regulates critical processes in innate immunity, but its role in parenchymal cells remains elusive in chronic liver diseases. We investigate the relative contribution of SYK and its substrate c-Abl Src homology 3 domain-binding protein-2 (3BP2) in both myeloid cells and hepatocytes in the onset of metabolic steatohepatitis. Methods: Hepatic SYK-3BP2 pathway was evaluated in mouse models of metabolic-associated fatty liver diseases (MAFLD) and in obese patients with biopsy-proven MAFLD (n = 33). Its role in liver complications was evaluated in Sh3bp2 KO and myeloid-specific Syk KO mice challenged with methionine and choline deficient diet and in homozygous Sh3bp2KI/KI mice with and without SYK expression in myeloid cells. Results: Here we report that hepatic expression of 3BP2 and SYK correlated with metabolic steatohepatitis severity in mice. 3BP2 deficiency and SYK deletion in myeloid cells mediated the same protective effects on liver inflammation, injury, and fibrosis priming upon diet-induced steatohepatitis. In primary hepatocytes, the targeting of 3BP2 or SYK strongly decreased the lipopolysaccharide-mediated inflammatory mediator expression and 3BP2-regulated SYK expression. In homozygous Sh3bp2KI/KI mice, the chronic inflammation mediated by the proteasome-resistant 3BP2 mutant promoted severe hepatitis and liver fibrosis with augmented liver SYK expression. In these mice, the deletion of SYK in myeloid cells was sufficient to prevent these liver lesions. The hepatic expression of SYK is also up-regulated with metabolic steatohepatitis and correlates with liver macrophages in biopsy-proven MAFLD patients. Conclusions: Collectively, these data suggest an important role for the SYK-3BP2 pathway in the pathogenesis of chronic liver inflammatory diseases and highlight its targeting in hepatocytes and myeloid cells as a potential strategy to treat metabolic steatohepatitis. |
| format |
article |
| author |
Carmelo Luci Elodie Vieira Manon Bourinet Déborah Rousseau Stéphanie Bonnafous Stéphanie Patouraux Lauren Lefevre Frederic Larbret Virginie Prod’homme Antonio Iannelli Albert Tran Rodolphe Anty Béatrice Bailly-Maitre Marcel Deckert Philippe Gual |
| author_facet |
Carmelo Luci Elodie Vieira Manon Bourinet Déborah Rousseau Stéphanie Bonnafous Stéphanie Patouraux Lauren Lefevre Frederic Larbret Virginie Prod’homme Antonio Iannelli Albert Tran Rodolphe Anty Béatrice Bailly-Maitre Marcel Deckert Philippe Gual |
| author_sort |
Carmelo Luci |
| title |
SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic SteatohepatitisSummary |
| title_short |
SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic SteatohepatitisSummary |
| title_full |
SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic SteatohepatitisSummary |
| title_fullStr |
SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic SteatohepatitisSummary |
| title_full_unstemmed |
SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic SteatohepatitisSummary |
| title_sort |
syk-3bp2 pathway activity in parenchymal and myeloid cells is a key pathogenic factor in metabolic steatohepatitissummary |
| publisher |
Elsevier |
| publishDate |
2022 |
| url |
https://doaj.org/article/7c2834e876ae418c87a2d3e981267d10 |
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