دورية أكاديمية
CXCR3A promotes the secretion of the antifibrotic decoy receptor sIL-13Rα2 by pulmonary fibroblasts.
| العنوان: | CXCR3A promotes the secretion of the antifibrotic decoy receptor sIL-13Rα2 by pulmonary fibroblasts. |
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| المؤلفون: | Worrell JC; St. Vincent's University Hospital and School of Medicine, University College Dublin and UCD Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland., Walsh SM; St. Vincent's University Hospital and School of Medicine, University College Dublin and UCD Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland.; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland., Fabre A; St. Vincent's University Hospital and School of Medicine, University College Dublin and UCD Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland.; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.; UCD Conway Research Pathology Core Technology, University College Dublin, Dublin, Ireland., Kane R; St. Vincent's University Hospital and School of Medicine, University College Dublin and UCD Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland., Hinz B; Laboratory of Tissue Repair and Regeneration, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada., Keane MP; St. Vincent's University Hospital and School of Medicine, University College Dublin and UCD Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland.; UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland. |
| المصدر: | American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2020 Dec 01; Vol. 319 (6), pp. C1059-C1069. Date of Electronic Publication: 2020 Oct 07. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901225 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1563 (Electronic) Linking ISSN: 03636143 NLM ISO Abbreviation: Am J Physiol Cell Physiol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, Md. : American Physiological Society, |
| مواضيع طبية MeSH: | Extracellular Matrix/*metabolism , Fibroblasts/*metabolism , Interleukin-13 Receptor alpha2 Subunit/*metabolism , Pulmonary Fibrosis/*pathology , Receptors, CXCR3/*metabolism, 3T3 Cells ; Animals ; Cell Line ; Cell Movement/physiology ; Cell Proliferation/physiology ; Female ; Interleukin-13/genetics ; Interleukin-13/metabolism ; Interleukin-13 Receptor alpha2 Subunit/genetics ; Lung/cytology ; Lung/metabolism ; Macrophages, Alveolar/immunology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mitogen-Activated Protein Kinase 1/metabolism ; Mitogen-Activated Protein Kinase 3/metabolism ; Transcription Factor RelA/metabolism |
| مستخلص: | 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-13Rα2. 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-13Rα2 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-κB-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 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. |
| معلومات مُعتمدة: | 375597 International Gouvernement du Canada | Canadian Institutes of Health Research (Instituts de recherche en santé du Canada) |
| فهرسة مساهمة: | Keywords: CXCR3A; collagen; contractility; fibroblast; fibrosis |
| المشرفين على المادة: | 0 (Cxcr3 protein, mouse) 0 (Interleukin-13) 0 (Interleukin-13 Receptor alpha2 Subunit) 0 (Receptors, CXCR3) 0 (Rela protein, mouse) 0 (Transcription Factor RelA) EC 2.7.11.24 (Mapk1 protein, mouse) EC 2.7.11.24 (Mapk3 protein, mouse) EC 2.7.11.24 (Mitogen-Activated Protein Kinase 1) EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) |
| تواريخ الأحداث: | Date Created: 20201007 Date Completed: 20210107 Latest Revision: 20210107 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1152/ajpcell.00076.2020 |
| PMID: | 33026833 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1522-1563 |
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| DOI: | 10.1152/ajpcell.00076.2020 |