biostudies-literatureTsoyi KNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNHLBI NIH HHSNational Heart, Lung, and Blood InstituteNIAMS NIH HHS2847https://www.ebi.ac.uk/biostudies/studies/S-EPMC8857282biostudies-literatureUnknown12(1)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 oScientific reportsSyndecan-2 regulates PAD2 to exert antifibrotic effects on RA-ILD fibroblasts.PMC8857282F32 HL151132R01 AR070171L30 HL149048K01 AR074558P01 HL114501Romero FXiong KRyter SWEl-Chemaly SYRosas IOLiang XSun BChu SGBeeton CCardenas REsposito AJPoli FBowen RGDoyle TJPerrella MATsoyi KHo ICCelada LJRobertson MJfalseSyndecan-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, 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 o2022-01-01T00:00:00Z2022 Feb2025-04-22T10:01:40.854Z2025-04-05T23:22:37.415ZS-EPMC88572823518168810.1038/s41598-022-06678-7