| First Author | Worrell JC | Year | 2020 |
| Journal | Am J Physiol Cell Physiol | Volume | 319 |
| Issue | 6 | Pages | C1059-C1069 |
| PubMed ID | 33026833 | Mgi Jnum | J:299948 |
| Mgi Id | MGI:6501444 | Doi | 10.1152/ajpcell.00076.2020 |
| Citation | Worrell JC, et al. (2020) CXCR3A promotes the secretion of the antifibrotic decoy receptor sIL-13Ralpha2 by pulmonary fibroblasts. Am J Physiol Cell Physiol 319(6):C1059-C1069 |
| abstractText | CXC chemokine receptor 3 (CXCR3) A and its IFN-inducible ligands CXCL9 and CXCL10 regulate vascular remodeling and fibroblast motility. IL-13 is a profibrotic cytokine implicated in the pathogenesis of inflammatory and fibroproliferative conditions. Previous work from our laboratory has shown that CXCR3A is negatively regulated by IL-13 and is necessary for the basal regulation of the IL-13 receptor subunit IL-13Ralpha2. This study investigates the regulation of fibroblast phenotype, function, and downstream IL-13 signaling by CXCR3A in vitro. CXCR3A was overexpressed via transient transfection. CXCR3A(-/-) lung fibroblasts were isolated for functional analysis. Additionally, the contribution of CXCR3A to tissue remodeling following acute lung injury was assessed in vivo with wild-type (WT) and CXCR3(-/-) mice challenged with IL-13. CXCR3 and IL-13Ralpha2 displayed a reciprocal relationship after 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 downregulation of NF-kappaB-p65. CXCR3A(-/-) pulmonary fibroblasts were increasingly proliferative and displayed reduced contractility and alpha-smooth muscle actin expression. IL-13 challenge regulated expression of the CXCR3 ligands and soluble IL-13Ralpha2 levels in lungs and bronchoalveolar lavage fluid (BALF) of WT mice; this response was absent in CXCR3(-/-) mice. Alveolar macrophage accumulation and expression of genes involved in lung remodeling was increased in CXCR3(-/-) mice. We conclude that CXCR3A is a central antifibrotic factor in pulmonary fibroblasts, limiting fibroblast activation and reducing extracellular matrix (ECM) production. Therefore, targeting of CXCR3A may be a novel approach to regulating fibroblast activity in lung fibrosis and remodeling. |
