SYK-3BP2 Pathway Activity in Parenchymal and Myeloid Cells Is a Key Pathogenic Factor in Metabolic Steatohepatitis.

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.

Natural Killer Cells and Type 1 Innate Lymphoid Cells Are New Actors in Non-alcoholic Fatty Liver Disease.

Obesity and associated liver diseases (Non Alcoholic Fatty Liver Disease, NAFLD) are a major public health problem with increasing incidence in Western countries (25% of the affected population). These complications develop from a fatty liver (steatosis) to an inflammatory state (steatohepatitis) evolving toward fibrosis and hepatocellular carcinoma. Lipid accumulation in the liver contributes to hepatocyte cell death and promotes liver injury. Local immune cells are activated either by Danger Associated Molecular Patterns (DAMPS) released by dead hepatocytes or by bacterial products (PAMPS) reaching the liver due to increased intestinal permeability. The resulting low-grade inflammatory state promotes the progression of liver complications toward more severe grades. Innate lymphoid cells (ILC) are an heterogeneous family of five subsets including circulating Natural Killer (NK) cells, ILC1, ILC2, ILC3, and lymphocytes tissue-inducer cells (LTi). NK cells and tissue-resident ILCs, mainly located at epithelial surfaces, are prompt to rapidly react to environmental changes to mount appropriate immune responses. Recent works have demonstrated the interplay between ILCs subsets and the environment within metabolic active organs such as liver, adipose tissue and gut during diet-induced obesity leading or not to hepatic abnormalities. Here, we provide an overview of the newly roles of NK cells and ILC1 in metabolism focusing on their contribution to the development of NAFLD. We also discuss recent studies that demonstrate the ability of these two subsets to influence tissue-specific metabolism and how their function and homeostasis are affected during metabolic disorders.