IL-17A Plays a Critical Role in the Pathogenesis of Liver Fibrosis through Hepatic Stellate Cell Activation

Abstract

Liver fibrosis is a severe, life-threatening clinical condition resulting from nonresolving hepatitis of different origins. IL-17A is critical in inflammation, but its relation to liver fibrosis remains elusive. We find increased IL-17A expression in fibrotic livers from HBV-infected patients undergoing partial hepatectomy because of cirrhosis-related early-stage hepatocellular carcinoma in comparison with control nonfibrotic livers from uninfected patients with hepatic hemangioma. In fibrotic livers, IL-17A immunoreactivity localizes to the inflammatory infiltrate. In experimental carbon tetrachloride–induced liver fibrosis of IL-17RA–deficient mice, we observe reduced neutrophil influx, proinflammatory cytokines, hepatocellular necrosis, inflammation, and fibrosis as compared with control C57BL/6 mice. IL-17A is produced by neutrophils and T lymphocytes expressing the Th17 lineage–specific transcription factor Retinoic acid receptor–related orphan receptor γt. Furthermore, hepatic stellate cells (HSCs) isolated from naive C57BL/6 mice respond to IL-17A with increased IL-6, α-smooth muscle actin, collagen, and TGF-β mRNA expression, suggesting an IL-17A–driven fibrotic process. Pharmacologic ERK1/2 or p38 inhibition significantly attenuated IL-17A–induced HSC activation and collagen expression. In conclusion, IL-17A+ Retinoic acid receptor–related orphan receptor γt+ neutrophils and T cells are recruited into the injured liver driving a chronic, fibrotic hepatitis. IL-17A–dependent HSC activation may be critical for liver fibrosis. Thus, blockade of IL-17A could potentially benefit patients with chronic hepatitis and liver fibrosis.

Interleukin-33 drives hepatic fibrosis through activation of hepatic stellate cells

“…34 Furthermore, ST2 signals via the JNK/ERK/p38-MAPK pathway, thereby regulating inflammation within innate lymphoid cells, macrophages and HSCs. 17,35,36 Because IL-33 has an important role in immune regulation, we aimed to verify whether the population of liver-infiltrating mononuclear cells is dependent on IL-33/ST2 signaling. We observed decreased Th1 cells, neutrophils and macrophages in ST2-KO mice, which could be due to the reduced hepatic injury and inflammation.…”

“…The role of IL-33 in HSC activation and liver fibrosis Z Tan et al HSC isolation and culture Primary mouse HSCs were isolated from livers of C57BL/6 mice according to a modified method previously described. 17 The isolated cells were plated on uncoated plastic at a density of 5 × 10 6 per 10-cm-diameter plate. After the first 24 h, nonadherent cells and debris were removed by washing.…”

Cellular Mechanisms of Tissue Fibrosis. 5. Novel insights into liver fibrosis

“…In the liver, the number of IL-17-positive cells is enhanced in patients with chronic hepatitis B or alcoholic liver disease and correlates with severity of fibrosis (48). Hepatic IL-17 levels are elevated in various experimental models of liver fibrosis, and mice deficient for IL-17 show resistance to liver fibrosis (21,60,83). IL-17 targets hepatic myofibroblasts by enhancing their proinflammatory and profibrogenic potential (21,48) and Kupffer cells by switching their phenotype towards M1 polarization (21).…”

PTPRO-Associated Hepatic Stellate Cell Activation Plays a Critical Role in Liver Fibrosis

“…Primary mouse HSCs were isolated from livers of C57BL/6 mice, as described previously, with modification [10]. Livers were perfused in situ with 45 ml Gibco Liver Perfusion Media (Invitrogen, Carlsbad, CA, USA) followed by 45 ml Gibco Liver Digestion Media (Invitrogen).…”

“…Fibrosis progression and regression need specific and complicated signaling pathways, including chemokines and cytokines such as platelet-derived growth factor (PDGF), transforming growth factor (TGF)-β and leptin [6,7,8]. Many recent studies have focused on the early events in liver fibrosis, such as immune interactions with interleukin (IL)-17 and IL-33 [9,10,11], but how they support fibrosis and activate HSCs requires verification.…”