{"doi":"10.1002/hep.32776","title":"Interleukin‐18 signaling promotes activation of hepatic stellate cells in mouse liver fibrosis","abstract":"BACKGROUND AND AIMS: Nucleotide-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 RESULTS: We 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. CONCLUSIONS: Our 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.","journal":"Hepatology","year":2022,"id":234974,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":88,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9641,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":226032,"name":"Benedikt Kaufmann","orcid":"0000-0002-8141-9676","position":1,"is_corresponding":false},{"id":851738,"name":"María Eugenia Inzaugarat","orcid":"0000-0001-9500-0123","position":2,"is_corresponding":false},{"id":851739,"name":"Theresa Maria Holtmann","orcid":"0000-0001-9007-1002","position":3,"is_corresponding":false},{"id":302634,"name":"Lukas Geisler","orcid":"0000-0001-5394-8004","position":4,"is_corresponding":false},{"id":851740,"name":"Jana Hundertmark","orcid":"0000-0001-7050-0797","position":5,"is_corresponding":false},{"id":579,"name":"Marlene Kohlhepp","orcid":"0000-0002-2828-1663","position":6,"is_corresponding":false},{"id":852355,"name":"Laela M. 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Loosen","orcid":"0000-0003-3447-1161","position":12,"is_corresponding":false},{"id":110022,"name":"Christian Trautwein","orcid":"0000-0003-2762-8247","position":13,"is_corresponding":false},{"id":752631,"name":"Christoph Roderburg","orcid":"0000-0002-1409-7697","position":14,"is_corresponding":false},{"id":245694,"name":"Münevver Demir","orcid":"0000-0002-7050-797X","position":15,"is_corresponding":false},{"id":569,"name":"Frank Tacke","orcid":"0000-0001-6206-0226","position":16,"is_corresponding":false},{"id":226040,"name":"Hal M. Hoffman","orcid":"0000-0001-8609-2548","position":17,"is_corresponding":false},{"id":302637,"name":"Ariel E. 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