Peptidylarginine deiminase 2 is required for tumor necrosis factor alpha-induced citrullination and arthritis, but not neutrophil extracellular trap formation

Abstract Citrullination, the post-translational conversion of arginines to citrullines, may contribute to rheumatoid arthritis development given the generation of anti-citrullinated protein antibodies (ACPAs). However, it is not known which peptidylarginine deiminase (PAD) catalyzes the citrullinati...

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Bibliographic Details
Published in:Journal of autoimmunity 2017-06, Vol.80, p.39-47
Main Authors: Bawadekar, Mandar, Shim, Daeun, Johnson, Chad J, Warner, Thomas F, Rebernick, Ryan, Damgaard, Dres, Nielsen, Claus H, Pruijn, Ger J.M, Nett, Jeniel E, Shelef, Miriam A
Format: Article
Language:English
Subjects:
Allergy and Immunology
Animals
Anti-Citrullinated Protein Antibodies - metabolism
Arthritis, Experimental - genetics
Arthritis, Experimental - immunology
Arthritis, Rheumatoid - immunology
Citrullination
Extracellular Traps - metabolism
Humans
Hydrolases - genetics
Hydrolases - metabolism
Immunoglobulin G - metabolism
Inflammation - immunology
Joints - metabolism
Joints - pathology
Mice
Mice, Knockout
Mice, Transgenic
Murine model
Neutrophil extracellular trap
Peptidylarginine deiminase
Plasma Cells - physiology
Protein-Arginine Deiminases - genetics
Protein-Arginine Deiminases - metabolism
Rheumatoid arthritis
TNFα
Tumor Necrosis Factor-alpha - genetics
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Summary:Abstract Citrullination, the post-translational conversion of arginines to citrullines, may contribute to rheumatoid arthritis development given the generation of anti-citrullinated protein antibodies (ACPAs). However, it is not known which peptidylarginine deiminase (PAD) catalyzes the citrullination seen in inflammation. PAD4 exacerbates inflammatory arthritis and is critical for neutrophil extracellular traps (NETs). NETs display citrullinated antigens targeted by ACPAs and thus may be a source of citrullinated protein. However, PAD4 is not required for citrullination in inflamed lungs. PAD2 is important for citrullination in healthy tissues and is present in NETs, but its role in citrullination in the inflamed joint, NETosis and inflammatory arthritis is unknown. Here we use mice with TNFα-induced inflammatory arthritis, a model of rheumatoid arthritis, to identify the roles of PAD2 and PAD4 in citrullination, NETosis, and arthritis. In mice with TNFα-induced arthritis, citrullination in the inflamed ankle was increased as determined by western blot. This increase was unchanged in the ankles of mice that lack PAD4. In contrast, citrullination was nearly absent in the ankles of PAD2-deficient mice. Interestingly, PAD2 was not required for NET formation as assessed by immunofluorescence or for killing of Candida albicans as determined by viability assay. Finally, plasma cell numbers as assessed by flow cytometry, IgG levels quantified by ELISA, and inflammatory arthritis as determined by clinical and pathological scoring were all reduced in the absence of PAD2. Thus, PAD2 contributes to TNFα-induced citrullination and arthritis, but is not required for NETosis. In contrast, PAD4, which is critical for NETosis, is dispensable for generalized citrullination supporting the possibility that NETs may not be a major source of citrullinated protein in arthritis.
ISSN:0896-8411
1095-9157
DOI:10.1016/j.jaut.2017.01.006