Inhibition of Sphingosine‐1‐Phosphate‐Induced Th17 Cells Ameliorates Alcohol‐Associated Steatohepatitis in Mice
- 1 March 2021
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Hepatology
- Vol. 73 (3), 952-967
- https://doi.org/10.1002/hep.31321
Abstract
Background and Aims Chronic alcohol consumption is accompanied by intestinal inflammation. However, little is known about how alterations to the intestinal immune system and sphingolipids contribute to the pathogenesis of alcohol‐associated liver disease (ALD). Approach and Results We used wild‐type mice, retinoid‐related orphan receptor gamma t (RORγt)‐deficient mice, sphingosine kinase–deficient mice, and local gut anti‐inflammatory, 5‐aminosalicyclic acid–treated mice in a chronic‐binge ethanol feeding model. Targeted lipidomics assessed the sphingolipids in gut and liver samples. Gut immune cell populations, the amounts of sphingolipids, and the level of liver injury were examined. Alcohol intake induces a pro‐inflammatory shift in immune cell populations in the gut, including an increase in Th17 cells. Using RORγt‐deficient mice, we found that Th17 cells are required for alcohol‐associated gut inflammation and the development of ALD. Treatment with 5‐aminosalicyclic acid decreases alcohol‐induced liver injury and reverses gut inflammation by the suppression of CD4+/RORγt+/interleukin‐17A+ cells. Increased Th17 cells were due to up‐regulation of sphingosine kinase 1 activity and RORγt activation. We found that S1P/S1PR1 signaling is required for the development of Th17 cell–mediated ALD. Importantly, in vivo intervention blocking of S1P/S1PR1 signaling markedly attenuated alcohol‐induced liver inflammation, steatosis, and damage. Conclusions Gut inflammation is a functional alteration of immune cells in ALD. Reducing gut Th17 cells leads to reduced liver damage. S1P signaling was crucial in the pathogenesis of ALD in a Th17 cell–dependent manner. Furthermore, our findings suggest that compounds that reduce gut inflammation locally may represent a unique targeted approach in the treatment of ALD.Funding Information
- National Institute of Allergy and Infectious Diseases (R21AI128206)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK115406)
- National Institute of General Medical Sciences (P20GM113226)
- National Institute on Alcohol Abuse and Alcoholism (R21AA025724, P50AA024337, U01AA026936, R01AA023190)
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