Syndecan-2 Regulates PAD2 To Exert Antifibrotic Effects on RA-ILD Fibroblasts

Authors

Konstantin Tsoyi
Anthony J Esposito
Bo Sun
Ryan G Bowen
Kevin Xiong
Fernando Poli
Rafael Cardenas
Sarah G Chu
Xiaoliang Liang
Stefan W Ryter
Christine Beeton
Tracy J Doyle
Matthew J Robertson
Lindsay J Celada
Freddy Romero
Souheil Y El-Chemaly
Mark A Perrella
I-Cheng Ho
Ivan O Rosas

Publication Date

2-18-2022

Journal

Scientific Reports

DOI

10.1038/s41598-022-06678-7

PMID

35181688

PMCID

PMC8857282

PubMedCentral® Posted Date

2-18-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

Animals, Anti-Citrullinated Protein Antibodies, Arthritis, Rheumatoid, Bleomycin, Citrullination, Fibroblasts, Gene Expression Regulation, Humans, Lung, Lung Injury, Mice, Mice, Transgenic, Phosphatidylinositol 3-Kinases, Protein-Arginine Deiminase Type 2, Proto-Oncogene Proteins c-akt, Pulmonary Fibrosis, Receptor-Like Protein Tyrosine Phosphatases, Class 3, Sp1 Transcription Factor, Syndecan-2, Respiratory tract diseases, Rheumatoid arthritis, Pathogenesis

Abstract

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.

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