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Reduced Anti-Histone Antibodies and Increased Risk of Rheumatoid Arthritis Associated with a Single Nucleotide Polymorphism in PADI4 in North Americans
Open AccessArticle

Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes

1
Department of Hematology, University Medical Center Groningen, University of Groningen, 9713GZ Groningen, The Netherlands
2
University of Exeter Medical School, Exeter EX1 2LU, UK
3
Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen (UMCG), 9713 GZ Groningen, The Netherlands
4
Department of Rheumatology, University Hospitals Bristol NHS Foundation Trust, Bristol BS1 3NU, UK
5
Rheumatology Department, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK
6
Institute for Cellular Medicine, Newcastle University & Sir William Leech Centre, The Freeman Hospital, Newcastle NE2 4HH, UK
7
Department of Rheumatology, Royal Cornwall Hospital Trust, Truro TR1 3UT, UK
8
UCB Celltech, Immunobone Therapeutic Area, Slough SL1 3WE, UK
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2019, 20(16), 4046; https://doi.org/10.3390/ijms20164046
Received: 2 July 2019 / Revised: 12 August 2019 / Accepted: 16 August 2019 / Published: 19 August 2019
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. View Full-Text
Keywords: rheumatoid arthritis; bronchiectasis; neutrophil; granulocytes; citrullination; inflammatory cytokines; peptidyl-arginine deiminase; galectin rheumatoid arthritis; bronchiectasis; neutrophil; granulocytes; citrullination; inflammatory cytokines; peptidyl-arginine deiminase; galectin
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Wiersma, V.R.; Clarke, A.; Pouwels, S.D.; Perry, E.; Abdullah, T.M.; Kelly, C.; Soyza, A.D.; Hutchinson, D.; Eggleton, P.; Bremer, E. Galectin-9 Is a Possible Promoter of Immunopathology in Rheumatoid Arthritis by Activation of Peptidyl Arginine Deiminase 4 (PAD-4) in Granulocytes. Int. J. Mol. Sci. 2019, 20, 4046.

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