Extracellular traps and PAD4 released by macrophages induce citrullination and auto-antibody production in autoimmune arthritis
The mechanisms underlying the transition of rheumatoid arthritis (RA) systemic autoimmunity to the joints remain largely unknown. Here, we demonstrate that macrophages in the secondary lymphoid organs (SLOs) and synovial ectopic lymphoid-like structures (ELSs) express peptidylarginine deiminase 4 (P...
Gespeichert in:
Veröffentlicht in: | Journal of autoimmunity 2019-12, Vol.105, p.102297, Article 102297 |
---|---|
Hauptverfasser: | , , , , , , , , |
Format: | Artikel |
Sprache: | eng |
Schlagworte: | |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | The mechanisms underlying the transition of rheumatoid arthritis (RA) systemic autoimmunity to the joints remain largely unknown. Here, we demonstrate that macrophages in the secondary lymphoid organs (SLOs) and synovial ectopic lymphoid-like structures (ELSs) express peptidylarginine deiminase 4 (PAD4) in murine collagen induced arthritis (CIA) and synovial biopsies from RA patients. Moreover, peptidyl citrulline colocalized with macrophages in SLOs and ELSs, and depletion of macrophages in CIA decreased lymphoid tissue citrullination and serum anti-citrullinated protein/peptide antibody (ACPA) levels. Furthermore, PAD was released from activated murine and RA synovial tissue and fluid (SF) macrophages which functionally deiminated extracellular proteins/peptides in vitro. Additionally, activated murine and SF macrophages displayed macrophage extracellular trap formation (METosis) and release of intracellular citrullinated histones. Moreover, presentation of citrullinated proteins induced ACPA production in vitro. Thus, lymphoid tissue macrophages contribute to self-antigen citrullination and ACPA production, indicating that their selective targeting would potentially ameliorate citrullination-dependent autoimmune disorders.
•Macrophage activation induces METosis and presentation of intracellular citrullinated histones.•Lymphoid tissue macrophages release PAD4 which citrullinates extracellular antigens.•Macrophages strongly correlate with B cells, T cells, and plasma cells in rheumatoid arthritis synovia.•Macrophage depletion in CIA mice correlates with reduced lymphoid tissue citrulline and systemic anti-CCP Abs.•Presentation of citrullinated antigens induces T-cell dependent anti-CCP Abs in in vitro germinal centre reactions. |
---|---|
ISSN: | 0896-8411 1095-9157 1095-9157 |
DOI: | 10.1016/j.jaut.2019.06.008 |