CXCR3A promotes the secretion of the anti-fibrotic decoy receptor sIL-13Rα2 by pulmonary fibroblasts

Worrell, J. C. , Walsh, S. M., Fabre, A., Kane, R., Hinz, B. and Keane, M. P. (2020) CXCR3A promotes the secretion of the anti-fibrotic decoy receptor sIL-13Rα2 by pulmonary fibroblasts. American Journal of Physiology: Cell Physiology, 319(6), C1059-C1069. (doi: 10.1152/ajpcell.00076.2020) (PMID:33026833)

Abstract

CXCR3A and its IFN-inducible ligands CXCL9 and CXCL10 regulate vascular remodelling and fibroblast motility. IL‑13 is a pro‑fibrotic cytokine implicated in the pathogenies of inflammatory and fibro-proliferative conditions. Previous work from our lab has shown that CXCR3A is negatively regulated by IL-13 and is necessary for the basal regulation of the IL-13 receptor subunit IL-13Rα2. This study investigates the regulation of fibroblast phenotype, function and downstream IL-13 signalling by CXCR3A in vitro. CXCR3A was overexpressed via transient transfection. CXCR3A-/- lung fibroblastswere isolated for functional analysis. Additionally, the contribution of CXCR3A to tissue remodelling following acute lung injury was assessed in vivo using wild type (WT) and CXCR3-/- mice challenged with IL-13. CXCR3 and IL‑13Rα2 displayed a reciprocal relationship following stimulation with either IL-13 or CXCR3 ligands. CXCR3A reduced expression of fibroblast activation makers, soluble collagen production and proliferation. CXCR3A enhanced the basal expression of pERK1/2 while inducing IL-13 mediated down‑regulation of NFκB‑p65. CXCR3A-/- pulmonary fibroblasts were increasingly proliferative and displayed reduced contractility and α‑smooth muscle actin expression. IL-13 challenge regulated expression of the CXCR3 ligands and soluble IL-13Rα2 levels in lungs and broncho‑alveolar lavage fluid (BALF) of WT mice, this response was absent in CXCR3-/- mice. Alveolar macrophage accumulation and expression of genes involved in lung remodelling was increased in CXCR3-/- mice. We conclude that CXCR3A is a central anti-fibrotic factor in pulmonary fibroblasts, limiting fibroblast activation and reducing ECM production. Therefore targeting of CXCR3A may be a novel approach to regulate fibroblast activity in lung fibrosis and remodelling.

• Item Type: Articles
• Additional Information: J.C.W was supported by Molecular Medicine Ireland Clinical and Translational Research Scholars Programme, funded under PRTLI Cycle 5 and ERDF. B. Hinz is supported by Canadian Institutes of Health Research Foundation Grant 375597.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Worrell, Dr Julie
• Authors: Worrell, J. C., Walsh, S. M., Fabre, A., Kane, R., Hinz, B., and Keane, M. P.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: American Journal of Physiology: Cell Physiology
• Publisher: American Physiological Society
• ISSN: 0363-6143
• ISSN (Online): 1522-1563
• Published Online: 07 October 2020
• Copyright Holders: Copyright © 2020 American Journal of Physiology-Cell Physiology
• First Published: First published in American Journal of Physiology: Cell Physiology 319(6):C1059-C1069
• Publisher Policy: Reproduced in accordance with the publisher copyright policy