Syndecan-2 regulates PAD2 to exert antifibrotic effects on RA-ILD fibroblasts

Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however,...

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Bibliographic Details
Published in:	Scientific reports Vol. 12; no. 1; pp. 2847 - 11
Main Authors:	Tsoyi, Konstantin, Esposito, Anthony J., Sun, Bo, Bowen, Ryan G., Xiong, Kevin, Poli, Fernando, Cardenas, Rafael, Chu, Sarah G., Liang, Xiaoliang, Ryter, Stefan W., Beeton, Christine, Doyle, Tracy J., Robertson, Matthew J., Celada, Lindsay J., Romero, Freddy, El-Chemaly, Souheil Y., Perrella, Mark A., Ho, I.-Cheng, Rosas, Ivan O.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 18-02-2022 Nature Publishing Group Nature Portfolio
Subjects:	692/420 692/699/1670/498 692/699/1785 AKT protein Animals Anti-Citrullinated Protein Antibodies - genetics Arthritis Arthritis, Rheumatoid - complications Arthritis, Rheumatoid - drug therapy Arthritis, Rheumatoid - genetics Arthritis, Rheumatoid - pathology Bleomycin Bleomycin - toxicity Citrullination - genetics Citrulline Extracellular matrix Fibroblasts Fibroblasts - metabolism Fibrosis Gene expression Gene Expression Regulation - genetics Humanities and Social Sciences Humans Inflammation Kinases Lung - metabolism Lung - pathology Lung diseases Lung Injury - chemically induced Lung Injury - complications Lung Injury - genetics Lung Injury - pathology Mice Mice, Transgenic Morbidity multidisciplinary Phosphatidylinositol 3-Kinases - genetics Protein-arginine deiminase Protein-Arginine Deiminase Type 2 - genetics Proteins Proteoglycans Proto-Oncogene Proteins c-akt - genetics Pulmonary Fibrosis - complications Pulmonary Fibrosis - drug therapy Pulmonary Fibrosis - genetics Pulmonary Fibrosis - pathology Receptor-Like Protein Tyrosine Phosphatases, Class 3 Rheumatoid arthritis Science Science (multidisciplinary) Sp1 protein Sp1 Transcription Factor - genetics Syndecan Syndecan-2 - genetics Therapeutic targets Transgenic mice
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Summary:	Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. Anti-citrullinated protein antibodies have been associated with the development and progression of both RA and fibrotic lung disease; however, the role of protein citrullination in RA-ILD remains unclear. Here, we demonstrate that the expression of peptidylarginine deiminase 2 (PAD2), an enzyme that catalyzes protein citrullination, is increased in lung homogenates from subjects with RA-ILD and their lung fibroblasts. Chemical inhibition or genetic knockdown of PAD2 in RA-ILD fibroblasts attenuated their activation, marked by decreased myofibroblast differentiation, gel contraction, and extracellular matrix gene expression. Treatment of RA-ILD fibroblasts with the proteoglycan syndecan-2 (SDC2) yielded similar antifibrotic effects through regulation of PAD2 expression, phosphoinositide 3-kinase/Akt signaling, and Sp1 activation in a CD148-dependent manner. Furthermore, SDC2-transgenic mice exposed to bleomycin-induced lung injury in an inflammatory arthritis model expressed lower levels of PAD2 and were protected from the development of pulmonary fibrosis. Together, our results support a SDC2-sensitive profibrotic role for PAD2 in RA-ILD fibroblasts and identify PAD2 as a promising therapeutic target of RA-ILD.
ISSN:	2045-2322 2045-2322
DOI:	10.1038/s41598-022-06678-7