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.

中文翻译：

---

巨噬细胞释放的细胞外陷阱和 PAD4 诱导自身免疫性关节炎中的瓜氨酸化和自身抗体的产生。

类风湿性关节炎（RA）系统性自身免疫向关节转变的机制仍然很大程度上未知。在这里，我们证明，在小鼠胶原诱导的关节炎 (CIA) 和 RA 患者的滑膜活检中，次级淋巴器官 (SLO) 和滑膜异位淋巴样结构 (ELS) 中的巨噬细胞表达肽基精氨酸脱亚胺酶 4 (PAD4)。此外，肽基瓜氨酸与 SLO 和 ELS 中的巨噬细胞共定位，并且 CIA 中巨噬细胞的耗竭降低了淋巴组织瓜氨酸化和血清抗瓜氨酸蛋白/肽抗体 (ACPA) 水平。此外，PAD 是从活化的小鼠和 RA 滑膜组织和液体 (SF) 巨噬细胞中释放出来的，这些巨噬细胞在体外功能性地使细胞外蛋白/肽脱亚氨基。此外，激活的小鼠和 SF 巨噬细胞显示巨噬细胞胞外陷阱形成 (METosis) 和胞内瓜氨酸组蛋白的释放。此外，瓜氨酸蛋白的呈递在体外诱导ACPA产生。因此，淋巴组织巨噬细胞有助于自身抗原瓜氨酸化和 ACPA 产生，表明它们的选择性靶向可能会改善瓜氨酸依赖性自身免疫性疾病。