Endoplasmic reticulum stress enhances fibrosis through IRE1α‐mediated degradation of miR‐150 and XBP‐1 splicing

• Published in: EMBO molecular medicine 2016-07, Vol.8 (7), p.729-744
• Main Authors: Heindryckx, Femke, Binet, François, Ponticos, Markella, Rombouts, Krista, Lau, Joey, Kreuger, Johan, Gerwins, Pär
• Format: Article
• Language: English
• Subjects: Animals; Cells, Cultured; EMBO12; EMBO28; EMBO38; Endoplasmic Reticulum Stress; Endoribonucleases - metabolism; fibrosis; Fibrosis - pathology; Humans; Liver - pathology; liver cirrhosis; Mice; MicroRNAs - metabolism; Molecular Medicine; Molekylär medicin; myofibroblast; Protein Serine-Threonine Kinases - metabolism; Research Article; scleroderma; Skin - pathology; Unfolded Protein Response; X-Box Binding Protein 1 - metabolism
• ISSN: 1757-4676; 1757-4684; 1757-4684
• DOI: 10.15252/emmm.201505925

ER stress results in activation of the unfolded protein response and has been implicated in the development of fibrotic diseases. In this study, we show that inhibition of the ER stress‐induced IRE1α signaling pathway, using the inhibitor 4μ8C, blocks TGFβ‐induced activation of myofibroblasts in vitro, reduces liver and skin fibrosis in vivo, and reverts the fibrotic phenotype of activated myofibroblasts isolated from patients with systemic sclerosis. By using IRE1α −/− fibroblasts and expression of IRE1α‐mutant proteins lacking endoribonuclease activity, we confirmed that IRE1α plays an important role during myofibroblast activation. IRE1α was shown to cleave miR‐150 and thereby to release the suppressive effect that miR‐150 exerted on αSMA expression through c‐Myb. Inhibition of IRE1α was also demonstrated to block ER expansion through an XBP‐1‐dependent pathway. Taken together, our results suggest that ER stress could be an important and conserved mechanism in the pathogenesis of fibrosis and that components of the ER stress pathway may be therapeutically relevant for treating patients with fibrotic diseases. Synopsis Endoplasmic reticulum (ER) stress is a conserved mechanism in the development of fibrosis. Targeting ER stress‐induced signaling might be a therapeutic strategy to combat fibrotic diseases. The RNase activity of the ER stress sensor IRE1α is required for activation of myofibroblasts. IRE1α mediates fibrosis by directly cleaving and inactivating miR‐150, which under nonfibrotic conditions represses expression of c‐Myb and αSMA. IRE1α‐mediated splicing of XBP‐1 is required for expansion of the ER in activated myofibroblasts. Pharmacological targeting of IRE1α with the small‐molecule inhibitor 4μ8C reduces liver and skin fibrosis in mouse models. 4μ8C reverts the fibrotic phenotype of myofibroblasts isolated from patients with systemic sclerosis. Graphical Abstract Endoplasmic reticulum (ER) stress is a conserved mechanism in the development of fibrosis. Targeting ER stress‐induced signaling might be a therapeutic strategy to combat fibrotic diseases.