1. Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis
- Author
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Knorr, Jana, Kaufmann, Benedikt, Inzaugarat, Maria Eugenia, Holtmann, Theresa Maria, Geisler, Lukas, Hundertmark, Jana, Kohlhepp, Marlene Sophia, Boosheri, Laela M, Chilin‐Fuentes, Daisy R, Birmingham, Amanda, Fisch, Kathleen M, Schilling, Joel D, Loosen, Sven H, Trautwein, Christian, Roderburg, Christoph, Demir, Münevver, Tacke, Frank, Hoffman, Hal M, Feldstein, Ariel E, and Wree, Alexander
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Immunology ,Liver Disease ,Digestive Diseases ,Nutrition ,Chronic Liver Disease and Cirrhosis ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Oral and gastrointestinal ,Mice ,Animals ,Inflammasomes ,Hepatic Stellate Cells ,Interleukin-18 ,NLR Family ,Pyrin Domain-Containing 3 Protein ,Liver Cirrhosis ,Fibrosis ,Carrier Proteins ,Liver ,Medical Biochemistry and Metabolomics ,Gastroenterology & Hepatology ,Clinical sciences - Abstract
Background and aimsNucleotide-binding oligomerization domain-like receptor-family pyrin domain-containing 3 (NLRP3) inflammasome activation has been shown to result in liver fibrosis. Mechanisms and downstream signaling remain incompletely understood. Here, we studied the role of IL-18 in hepatic stellate cells (HSCs), and its impact on liver fibrosis.Approach and resultsWe observed significantly increased serum levels of IL-18 (128.4 pg/ml vs. 74.9 pg/ml) and IL-18 binding protein (BP; 46.50 ng/ml vs. 15.35 ng/ml) in patients with liver cirrhosis compared with healthy controls. Single cell RNA sequencing data showed that an immunoregulatory subset of murine HSCs highly expresses Il18 and Il18r1 . Treatment of cultured primary murine HSC with recombinant mouse IL-18 accelerated their transdifferentiation into myofibroblasts. In vivo , IL-18 receptor-deficient mice had reduced liver fibrosis in a model of fibrosis induced by HSC-specific NLRP3 overactivation. Whole liver RNA sequencing analysis from a murine model of severe NASH-induced fibrosis by feeding a choline-deficient, L-amino acid-defined, high fat diet showed that genes related to IL-18 and its downstream signaling were significantly upregulated, and Il18-/- mice receiving this diet for 10 weeks showed protection from fibrotic changes with decreased number of alpha smooth muscle actin-positive cells and collagen deposition. HSC activation triggered by NLRP3 inflammasome activation was abrogated when IL-18 signaling was blocked by its naturally occurring antagonist IL-18BP. Accordingly, we observed that the severe inflammatory phenotype associated with myeloid cell-specific NLRP3 gain-of-function was rescued by IL-18BP.ConclusionsOur study highlights the role of IL-18 in the development of liver fibrosis by its direct effect on HSC activation identifying IL-18 as a target to treat liver fibrosis.
- Published
- 2023