{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T15:43:47Z","timestamp":1790264627837,"version":"4.1.0"},"reference-count":67,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2019,8,19]],"date-time":"2019-08-19T00:00:00Z","timestamp":1566172800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004622","name":"KWF Kankerbestrijding","doi-asserted-by":"publisher","award":["10709"],"award-info":[{"award-number":["10709"]}],"id":[{"id":"10.13039\/501100004622","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000341","name":"Arthritis Research UK","doi-asserted-by":"publisher","award":["19894"],"award-info":[{"award-number":["19894"]}],"id":[{"id":"10.13039\/501100000341","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The aetiology of rheumatoid arthritis (RA) is unknown, but citrullination of proteins is thought to be an initiating event. In addition, it is increasingly evident that the lung can be a potential site for the generation of autoimmune triggers before the development of joint disease. Here, we identified that serum levels of galectin-9 (Gal-9), a pleiotropic immunomodulatory protein, are elevated in RA patients, and are even further increased in patients with comorbid bronchiectasis, a lung disease caused by chronic inflammation. The serum concentrations of Gal-9 correlate with C-reactive protein levels and DAS-28 score. Gal-9 activated polymorphonuclear leukocytes (granulocytes) in vitro, which was characterized by increased cytokine secretion, migration, and survival. Further, granulocytes treated with Gal-9 upregulated expression of peptidyl arginine deiminase 4 (PAD-4), a key enzyme required for RA-associated citrullination of proteins. Correspondingly, treatment with Gal-9 triggered citrullination of intracellular granulocyte proteins that are known contributors to RA pathogenesis (i.e., myeloperoxidase, alpha-enolase, MMP-9, lactoferrin). In conclusion, this study identifies for the first time an immunomodulatory protein, Gal-9, that triggers activation of granulocytes leading to increased PAD-4 expression and generation of citrullinated autoantigens. This pathway may represent a potentially important mechanism for development of RA.<\/jats:p>","DOI":"10.3390\/ijms20164046","type":"journal-article","created":{"date-parts":[[2019,8,19]],"date-time":"2019-08-19T11:22:38Z","timestamp":1566213758000},"page":"4046","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes"],"prefix":"10.3390","volume":"20","author":[{"given":"Valerie R.","family":"Wiersma","sequence":"first","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Clarke","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, Exeter EX1 2LU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7345-8061","authenticated-orcid":false,"given":"Simon D.","family":"Pouwels","sequence":"additional","affiliation":[{"name":"Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Perry","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospitals Bristol NHS Foundation Trust, Bristol BS1 3NU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trefa M.","family":"Abdullah","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, Exeter EX1 2LU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clive","family":"Kelly","sequence":"additional","affiliation":[{"name":"Rheumatology Department, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony De","family":"Soyza","sequence":"additional","affiliation":[{"name":"Institute for Cellular Medicine, Newcastle University &amp; Sir William Leech Centre, The Freeman Hospital, Newcastle NE2 4HH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hutchinson","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, Royal Cornwall Hospital Trust, Truro TR1 3UT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Eggleton","sequence":"additional","affiliation":[{"name":"University of Exeter Medical School, Exeter EX1 2LU, UK"},{"name":"UCB Celltech, Immunobone Therapeutic Area, Slough SL1 3WE, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8244-2125","authenticated-orcid":false,"given":"Edwin","family":"Bremer","sequence":"additional","affiliation":[{"name":"Department of Hematology, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands"},{"name":"University of Exeter Medical School, Exeter EX1 2LU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,8,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/nri2536","article-title":"Turning \u2018sweet\u2019 on immunity: Galectin-glycan interactions in immune tolerance and inflammation","volume":"9","author":"Rabinovich","year":"2009","journal-title":"Nat. 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