Key Points Intestinal DCs migrate to RLN on ReA onset. TNFRp55 deficiency promotes CCR7 expression. FTY720 reduces DC migration and suppresses ReA. Visual Abstract Dendritic cells (DCs) participate in the pathogenesis of several diseases. We investigated DCs and the connection between mucosa and joints in a murine model of Yersinia enterocolitica O:3–induced reactive arthritis (ReA) in TNFRp55−/− mice. DCs of mesenteric lymph nodes (MLN) and joint regional lymph nodes (RLN) were analyzed in TNFRp55−/− and wild-type mice. On day 14 after Y. enterocolitica infection (arthritis onset), we found that under TNFRp55 deficiency, migratory (MHChighCD11c+) DCs increased significantly in RLN. Within these RLN, resident (MHCintCD11c+) DCs increased on days 14 and 21. Similar changes in both migratory and resident DCs were also detected on day 14 in MLN of TNFRp55−/− mice. In vitro, LPS-stimulated migratory TNFRp55−/− DCs of MLN increased IL-12/23p40 compared with wild-type mice. In addition, TNFRp55−/− bone marrow–derived DCs in a TNFRp55−/− MLN microenvironment exhibited higher expression of CCR7 after Y. enterocolitica infection. The major intestinal DC subsets (CD103+CD11b−, CD103−CD11b+, and CD103+CD11b+) were found in the RLN of Y. enterocolitica–infected TNFRp55−/− mice. Fingolimod (FTY720) treatment of Y. enterocolitica–infected mice reduced the CD11b− subset of migratory DCs in RLN of TNFRp55−/− mice and significantly suppressed the severity of ReA in these mice. This result was associated with decreased articular IL-12/23p40 and IFN-γ levels. In vitro FTY720 treatment downregulated CCR7 on Y. enterocolitica–infected bone marrow–derived DCs and purified MLN DCs, which may explain the mechanism underlying the impairment of DCs in RLN induced by FTY720. Taken together, data indicate the migration of intestinal DCs to RLN and the contribution of these cells in the immunopathogenesis of ReA, which may provide evidence for controlling this disease.

中文翻译：

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肠系膜和区域淋巴结的树突细胞导致 TNFRp55−/− 小鼠小肠结肠炎耶尔森氏菌 O:3 诱导的反应性关节炎

关键点肠道 DC 在 ReA 发作时迁移到 RLN。TNFRp55 缺乏促进 CCR7 表达。FTY720 减少 DC 迁移并抑制 ReA。Visual Abstract 树突状细胞 (DC) 参与多种疾病的发病机制。我们在 TNFRp55-/- 小鼠中研究了小肠结肠炎耶尔森氏菌 O:3 诱导的反应性关节炎 (ReA) 小鼠模型中的 DC 以及粘膜和关节之间的联系。在 TNFRp55-/- 和野生型小鼠中分析肠系膜淋巴结 (MLN) 和关节区域淋巴结 (RLN) 的 DC。在小肠结肠炎耶尔森氏菌感染（关节炎发作）后第 14 天，我们发现在 TNFRp55 缺乏下，RLN 中的迁移性（MHChighCD11c+）DC 显着增加。在这些 RLN 中，常驻 (MHCintCD11c+) DC 在第 14 天和第 21 天增加。在第 14 天，在 TNFRp55-/- 小鼠的 MLN 中也检测到迁移和驻留 DC 的类似变化。在体外，与野生型小鼠相比，LPS 刺激的 MLN 的迁移性 TNFRp55-/- DCs 增加了 IL-12/23p40。此外，在 TNFRp55-/- MLN 微环境中，TNFRp55-/- 骨髓来源的 DC 在小肠结肠炎耶尔森氏菌感染后表现出更高的 CCR7 表达。在小肠结肠炎耶尔森氏菌感染的 TNFRp55-/- 小鼠的 RLN 中发现了主要的肠道 DC 亚群（CD103+CD11b-、CD103-CD11b+ 和 CD103+CD11b+）。芬戈莫德 (FTY720) 治疗小肠结肠炎耶尔森氏菌感染的小鼠减少了 TNFRp55-/- 小鼠 RLN 中迁移性 DC 的 CD11b- 子集，并显着抑制了这些小鼠 ReA 的严重程度。该结果与关节 IL-12/23p40 和 IFN-γ 水平降低有关。体外 FTY720 处理下调 Y 上的 CCR7。小肠结肠炎感染的骨髓来源的 DCs 和纯化的 MLN DCs，这可能解释了 FTY720 诱导的 RLN 中 DCs 损伤的潜在机制。综上所述，数据表明肠道 DCs 向 RLN 迁移以及这些细胞在 ReA 免疫发病机制中的贡献，这可能为控制该疾病提供证据。