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Worrell JC;Walsh SM;Fabre A;Kane R;Hinz B;Keane MP;
American Journal Of Physiology: Cell Physiology
CXCR3A promotes the secretion of the anti-fibrotic decoy receptor sIL-13R¿2 by pulmonary fibroblasts.
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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-13R¿2. 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¿13R¿2 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 NF¿B¿p65. CXCR3A-/- pulmonary fibroblasts were increasingly proliferative and displayed reduced contractility and ¿¿smooth muscle actin expression. IL-13 challenge regulated expression of the CXCR3 ligands and soluble IL-13R¿2 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.
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