{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T07:50:07Z","timestamp":1773561007501,"version":"3.50.1"},"reference-count":29,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T00:00:00Z","timestamp":1773532800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T00:00:00Z","timestamp":1773532800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL158601"],"award-info":[{"award-number":["HL158601"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HL 168138"],"award-info":[{"award-number":["HL 168138"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100002590","name":"American Lung Association","doi-asserted-by":"publisher","award":["DA\u2010827785"],"award-info":[{"award-number":["DA\u2010827785"]}],"id":[{"id":"10.13039\/100002590","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"abstract":"\n Abstract<\/jats:title>\n \n Fibroblasts exhibit organ\u2010specific function and in response to tumour necrosis factor \u03b1 (TNF\u03b1) can produce a large amount of inflammatory mediators, including interleukin\u20106 (IL\u20106), partly via a leukaemia inhibitory factor (LIF) autocrine loop, thereby playing a critical pathogenic role in several organ\u2010specific autoimmune diseases, such as rheumatoid arthritis (RA). Peptidylarginine deiminases (PADs), including PAD1\u20104 and PAD6 in humans, irreversibly convert peptidylarginine to non\u2010coding peptidylcitrulline, a process also known as citrullination. Although the behaviour of fibroblasts is influenced by the citrullination status of extracellular matrix proteins, whether PADs cell\u2010autonomously regulate gene expression of fibroblasts is still unclear. Interestingly heightened PAD activity is strongly associated with RA, which often co\u2010occurs with interstitial lung disease (ILD). The molecular mechanism mediating the unique lung\u2013synovium connection in RA is still poorly understood. Here we show that PAD2 transcript levels in lung fibroblasts (LFs) increased with age, a trend not observed with other PADs or in fibroblasts from other organs. PAD2 deficiency reduced the expression of Podoplanin and Tumor necrosis factor receptor superfamily member 1B (TNFRSF1b) across fibroblasts from all mouse organs and human LFs. Additionally PAD2 deficiency attenuated the expression of several LIF\u2010dependent and LIF\u2010independent genes, including chemokines and\n Il6<\/jats:italic>\n , in LFs after TNF\u03b1 stimulation. Particularly a reduction in TNF\u03b1\u2010induced interleukin\u20106 (IL\u20106) expression was also detected in fibroblasts from synovium but not in fibroblasts from other organs. These findings demonstrate that PAD2 regulates TNF\u03b1\u2010induced gene expression of fibroblasts depending on their organ origin, suggest a novel pathogenic role for PAD2 in RA and offer a plausible explanation for the observed lung\u2013synovium connection.\n \n \n image<\/jats:alt-text>\n <\/jats:graphic>\n <\/jats:boxed-text>\n <\/jats:p>\n <\/jats:sec>\n \n Key points<\/jats:title>\n \n \n \n Fibroblasts in response to tumour necrosis factor \u03b1 (TNF\u03b1) produce a high level of inflammatory cytokine interleukin\u20106 (IL\u20106) that drives the joint and often lung inflammation seen in rheumatoid arthritis (RA), which is characterized by autoimmunity against citrullinated antigens produced by peptidylarginine deiminases (PADs).<\/jats:p>\n <\/jats:list-item>\n \n Fibroblast\u2010derived PAD2 can citrullinate extracellular matrix proteins (ECMPs), whereas the citrullination status of ECMPs reciprocally influences the behaviour of fibroblasts.<\/jats:p>\n <\/jats:list-item>\n \n We examined the cell\u2010autonomous role of PAD2 in fibroblast gene expression and found that PAD2 levels uniquely increase with age in lung fibroblasts (LFs) but not fibroblasts from other organs.<\/jats:p>\n <\/jats:list-item>\n \n PAD2\u00a0maintains the expression of Podoplanin and Tumor necrosis factor receptor superfamily member 1B (TNFRSF1b) in fibroblasts across multiple organs but promotes basal and TNF\u03b1\u2010induced IL\u20106 expression in lung and synovial fibroblasts.<\/jats:p>\n <\/jats:list-item>\n \n These results suggest a novel pathogenic role for fibroblast\u2010derived PAD2 in RA and offer a plausible explanation for the unique tissue tropism of RA.<\/jats:p>\n <\/jats:list-item>\n <\/jats:list>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1113\/jp290391","type":"journal-article","created":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T07:21:14Z","timestamp":1773559274000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Regulation of basal and tumour necrosis factor \u03b1\u2010induced fibroblast gene expression by peptidylarginine deiminase 2"],"prefix":"10.1113","author":[{"given":"Mohammad Aslam","family":"Saifi","sequence":"first","affiliation":[{"name":"Division of Rheumatology, Inflammation, and Immunity, Department of Medicine Brigham and Women's Hospital Boston Massachusetts USA"},{"name":"Harvard Medical School Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Flavien","family":"Marguerie","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Inflammation, and Immunity, Department of Medicine Brigham and Women's Hospital Boston Massachusetts USA"},{"name":"Harvard Medical School Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mari","family":"Kamiya","sequence":"additional","affiliation":[{"name":"Harvard Medical School Boston Massachusetts USA"},{"name":"Division of Pulmonary and Critical Care, Department of Medicine Brigham and Women's Hospital Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung N.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Inflammation, and Immunity, Department of Medicine Brigham and Women's Hospital Boston Massachusetts USA"},{"name":"Harvard Medical School Boston Massachusetts USA"},{"name":"Division of Pulmonary and Critical Care, Department of Medicine Brigham and Women's Hospital Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachel S.","family":"Knipe","sequence":"additional","affiliation":[{"name":"Harvard Medical School Boston Massachusetts USA"},{"name":"Division of Pulmonary and Critical Care Medicine, Department of Medicine Massachusetts General Hospital Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edy Y.","family":"Kim","sequence":"additional","affiliation":[{"name":"Harvard Medical School Boston Massachusetts USA"},{"name":"Division of Pulmonary and Critical Care, Department of Medicine Brigham and Women's Hospital Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"I\u2010Cheng","family":"Ho","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Inflammation, and Immunity, Department of Medicine Brigham and Women's Hospital Boston Massachusetts USA"},{"name":"Harvard Medical School Boston Massachusetts USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2026,3,15]]},"reference":[{"issue":"5","key":"e_1_2_5_2_1","doi-asserted-by":"crossref","first-page":"C1179","DOI":"10.1152\/ajpcell.00054.2023","article-title":"Passing the post: Roles of posttranslational modifications in the form and function of extracellular matrix","volume":"324","author":"Adams J. C.","year":"2023","journal-title":"American Journal of Physiology\u2010Cell Physiology"},{"issue":"7860","key":"e_1_2_5_3_1","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41586-021-03549-5","article-title":"Cross\u2010tissue organization of the fibroblast lineage","volume":"593","author":"Buechler M. B.","year":"2021","journal-title":"Nature"},{"issue":"9","key":"e_1_2_5_4_1","doi-asserted-by":"crossref","first-page":"2323","DOI":"10.1002\/art.39215","article-title":"The W620 polymorphism in PTPN22 disrupts its interaction with peptidylarginine deiminase type 4 and enhances citrullination and NETosis","volume":"67","author":"Chang H. H.","year":"2015","journal-title":"Arthritis Rheumatol"},{"issue":"17","key":"e_1_2_5_5_1","article-title":"A molecular signature of preclinical rheumatoid arthritis triggered by dysregulated PTPN22","volume":"1","author":"Chang H. H.","year":"2016","journal-title":"Journal of Clinical Investigation Insight"},{"key":"e_1_2_5_6_1","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.71008","article-title":"Adult mouse fibroblasts retain organ\u2010specific transcriptomic identity","volume":"11","author":"Forte E.","year":"2022","journal-title":"eLife"},{"issue":"10","key":"e_1_2_5_7_1","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1016\/j.ccell.2024.08.020","article-title":"Cross\u2010tissue human fibroblast atlas reveals myofibroblast subtypes with distinct roles in immune modulation","volume":"42","author":"Gao Y.","year":"2024","journal-title":"Cancer Cell"},{"key":"e_1_2_5_8_1","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2023.1290585","article-title":"Peptidylarginine deiminase 2 citrullinates MZB1 and promotes the secretion of IgM and IgA","volume":"14","author":"Geary B.","year":"2023","journal-title":"Frontiers in Immunology"},{"issue":"19","key":"e_1_2_5_9_1","doi-asserted-by":"crossref","first-page":"12717","DOI":"10.1074\/jbc.M709508200","article-title":"Diversity in tissue expression, substrate binding, and SCF complex formation for a lectin family of ubiquitin ligases","volume":"283","author":"Glenn K. A.","year":"2008","journal-title":"Journal of Biological Chemistry"},{"issue":"7","key":"e_1_2_5_10_1","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/j.medj.2022.05.002","article-title":"Cross\u2010tissue, single\u2010cell stromal atlas identifies shared pathological fibroblast phenotypes in four chronic inflammatory diseases","volume":"3","author":"Korsunsky I.","year":"2022","journal-title":"Med"},{"issue":"10","key":"e_1_2_5_11_1","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1136\/ard.2007.075192","article-title":"Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells","volume":"67","author":"Makrygiannakis D.","year":"2008","journal-title":"Annals of the Rheumatic Diseases"},{"issue":"2","key":"e_1_2_5_12_1","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/leu.2016.187","article-title":"Citrullination of histone H3 drives IL\u20106 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma","volume":"31","author":"McNee G.","year":"2017","journal-title":"Leukemia"},{"issue":"11","key":"e_1_2_5_13_1","doi-asserted-by":"crossref","first-page":"3522","DOI":"10.1002\/art.34595","article-title":"Porphyromonas gingivalis and disease\u2010related autoantibodies in individuals at increased risk of rheumatoid arthritis","volume":"64","author":"Mikuls T. R.","year":"2012","journal-title":"Arthritis and Rheumatism"},{"issue":"2","key":"e_1_2_5_14_1","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.immuni.2017.01.004","article-title":"Autocrine loop involving IL\u20106 family member LIF, LIF receptor, and STAT4 drives sustained fibroblast production of inflammatory mediators","volume":"46","author":"Nguyen H. N.","year":"2017","journal-title":"Immunity"},{"issue":"1","key":"e_1_2_5_15_1","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1093\/rheumatology\/kes262","article-title":"A study of baseline prevalence and cumulative incidence of comorbidity and extra\u2010articular manifestations in RA and their impact on outcome","volume":"52","author":"Norton S.","year":"2013","journal-title":"Rheumatology"},{"issue":"2","key":"e_1_2_5_16_1","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1016\/S0002-9440(10)62263-8","article-title":"Insulin\u2010like growth factor binding proteins 3 and 5 are overexpressed in idiopathic pulmonary fibrosis and contribute to extracellular matrix deposition","volume":"166","author":"Pilewski J. M.","year":"2005","journal-title":"American Journal of Pathology"},{"issue":"2","key":"e_1_2_5_17_1","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1007\/s00296-025-05789-4","article-title":"The global prevalence of interstitial lung disease in patients with rheumatoid arthritis: A systematic review and meta\u2010analysis","volume":"45","author":"Prasanna H.","year":"2025","journal-title":"Rheumatology International"},{"issue":"2","key":"e_1_2_5_18_1","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1002\/cne.21055","article-title":"Experimental autoimmune encephalomyelitis induction in peptidylarginine deiminase 2 knockout mice","volume":"498","author":"Raijmakers R.","year":"2006","journal-title":"Journal of Comparative Neurology"},{"issue":"1890","key":"e_1_2_5_19_1","doi-asserted-by":"crossref","DOI":"10.1098\/rstb.2022.0244","article-title":"Citrullination of matrisomal proteins in health and diseases","volume":"378","author":"Saifi M. A.","year":"2023","journal-title":"Philosophical Transactions of the Royal Society of London. Series B: Biological Sciences"},{"issue":"3","key":"e_1_2_5_20_1","doi-asserted-by":"crossref","DOI":"10.1016\/j.rpth.2025.102866","article-title":"C\u2010type lectin\u2010like receptor 2 in platelets amplifies inflammation in rheumatoid arthritis","volume":"9","author":"Sasaki T.","year":"2025","journal-title":"Research and Practice in Thrombosis and Haemostasis"},{"issue":"24","key":"e_1_2_5_21_1","article-title":"E4 engages uPAR and enolase\u20101 and activates urokinase to exert antifibrotic effects","volume":"6","author":"Sharma S.","year":"2021","journal-title":"Journal of Clinical InvestigationInsight"},{"issue":"10","key":"e_1_2_5_22_1","doi-asserted-by":"crossref","first-page":"5532","DOI":"10.1073\/pnas.1912702117","article-title":"CUX1 and IkappaBzeta (NFKBIZ) mediate the synergistic inflammatory response to TNF and IL\u201017A in stromal fibroblasts","volume":"117","author":"Slowikowski K.","year":"2020","journal-title":"Proceedings of the National Academy of Sciences"},{"issue":"22","key":"e_1_2_5_23_1","article-title":"Reciprocal regulation of Th2 and Th17 cells by PAD2\u2010mediated citrullination","volume":"4","author":"Sun B.","year":"2019","journal-title":"Journal of Clinical Investigation Insight"},{"issue":"12","key":"e_1_2_5_24_1","doi-asserted-by":"crossref","DOI":"10.1126\/sciimmunol.aal3062","article-title":"Citrullination of NF\u2010kappaB p65 promotes its nuclear localization and TLR\u2010induced expression of IL\u20101beta and TNFalpha","volume":"2","author":"Sun B.","year":"2017","journal-title":"Science Immunology"},{"key":"e_1_2_5_25_1","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.matbio.2021.07.001","article-title":"PAD2\u2010mediated citrullination of fibulin\u20105 promotes elastogenesis","volume":"102","author":"Sun B.","year":"2021","journal-title":"Matrix Biology"},{"issue":"11","key":"e_1_2_5_26_1","doi-asserted-by":"crossref","first-page":"4535","DOI":"10.1093\/rheumatology\/keac124","article-title":"TNFR2 is critical for TNF\u2010induced rheumatoid arthritis fibroblast\u2010like synoviocyte inflammation","volume":"61","author":"Suto T.","year":"2022","journal-title":"Rheumatology"},{"issue":"1","key":"e_1_2_5_27_1","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1038\/s41598-022-06678-7","article-title":"Syndecan\u20102 regulates PAD2 to exert antifibrotic effects on RA\u2010ILD fibroblasts","volume":"12","author":"Tsoyi K.","year":"2022","journal-title":"Scientific Reports"},{"issue":"11","key":"e_1_2_5_28_1","doi-asserted-by":"crossref","first-page":"1177","DOI":"10.1164\/rccm.202305-0924OC","article-title":"Activation of CD8(+) T cells in chronic obstructive pulmonary disease lung","volume":"208","author":"Villasenor\u2010Altamirano A. B.","year":"2023","journal-title":"American Journal of Respiratory and Critical Care Medicine"},{"issue":"7","key":"e_1_2_5_29_1","doi-asserted-by":"crossref","first-page":"700","DOI":"10.2174\/1389450116666150202160954","article-title":"Protein arginine deiminases and associated citrullination: Physiological functions and diseases associated with dysregulation","volume":"16","author":"Witalison E. E.","year":"2015","journal-title":"Current Drug Targets"},{"key":"e_1_2_5_30_1","doi-asserted-by":"crossref","first-page":"3561","DOI":"10.2147\/JIR.S366620","article-title":"The role of podoplanin in the immune system and inflammation","volume":"15","author":"Zhang Z.","year":"2022","journal-title":"Journal of Inflammation Research"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP290391","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/full-xml\/10.1113\/JP290391","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP290391","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,15]],"date-time":"2026-03-15T07:21:18Z","timestamp":1773559278000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP290391"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,15]]},"references-count":29,"alternative-id":["10.1113\/JP290391"],"URL":"https:\/\/doi.org\/10.1113\/jp290391","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,15]]},"assertion":[{"value":"2025-10-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-15","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"JP290391"}}