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.
Highlights
Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-Interstitial lung disease (ILD)) is the most common pulmonary complication of RA, increasing morbidity and mortality
We found that PADI2 expression was elevated in sorted mesenchymal cells and cultured fibroblasts derived from RA-ILD lung (Fig. 1B,C)
To study the in vivo role of SDC2 in RA-ILD, we developed a two-hit model in which we utilized the combination of collagen antibody-induced arthritis (CAIA)[37], a previously validated mouse model of inflammatory arthritis characterized by administration of collagen type II autoantibodies and lipopolysaccharide (LPS)[38,39,40], followed by lung injury with bleomycin to induce pulmonary fibrosis (Supplementary Fig. S6 online)
Summary
Rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD) is the most common pulmonary complication of RA, increasing morbidity and mortality. 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. 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. We hypothesized that PAD2 contributes to the pathogenesis of RA-ILD by inducing a profibrotic phenotype in fibroblasts that is abrogated by SDC2 via CD148-dependent inhibition of PI3K/Akt/Sp1 signaling. We demonstrate that SDC2-transgenic mice express lower levels of PAD2 and are protected from lung fibrosis after bleomycin-induced lung injury in a model of inflammatory arthritis
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