In rheumatoid arthritis (RA), synovial tissue abundantly expresses CCL21, a chemokine strongly associated with RA susceptibility. In this study, we aimed to characterize the functional significance of CCL21/CCR7 signaling in different phases of RA pathogenesis. We determined that CCR7 is a hallmark of RA M1 synovial fluid (SF) macrophages, and its expression in RA monocytes and in vitro differentiated macrophages is closely associated with disease activity score (DAS28). In early stages of RA, monocytes infiltrate the synovial tissue. However, blockade of SF CCL21 or CCR7 prevents RA SF-mediated monocyte migration. CCR7 expression in the newly migrated macrophages can be accentuated by LPS and IFNγ and suppressed by IL-4 treatment. We also uncovered that CCL21 stimulation increases the number of M1-polarized macrophages (CD14+CD86+), resulting in elevated transcription of IL-6 and IL-23. These CCL21-induced M1 cytokines differentiate naïve T cells to Th17 cells, without affecting Th1 cell polarization. In the erosive stages of disease, CCL21 potentiates RA osteoclastogenesis through M1-driven Th17 polarization. Disruption of this intricate crosstalk, by blocking IL-6, IL-23, or IL-17 function, impairs the osteoclastogenic capacity of CCL21. Consistent with our in vitro findings, we establish that arthritis mediated by CCL21 expands the joint inflammation to bone erosion by connecting the differentiation of M1 macrophages with Th17 cells. Disease progression is further exacerbated by CCL21-induced neovascularization. We conclude that CCL21 is an attractive novel target for RA therapy, as blockade of its function may abrogate erosive arthritis modulated by M1 macrophages and Th17 cell crosstalk.

中文翻译：

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巨噬细胞中的 CCL21/CCR7 信号促进类风湿性关节炎中的关节炎症和 Th17 介导的破骨细胞形成。

在类风湿性关节炎 (RA) 中，滑膜组织大量表达 CCL21，这是一种与 RA 易感性密切相关的趋化因子。在这项研究中，我们旨在描述 CCL21/CCR7 信号在 RA 发病机制不同阶段的功能意义。我们确定 CCR7 是 RA M1 滑液 (SF) 巨噬细胞的标志，其在 RA 单核细胞和体外分化的巨噬细胞中的表达与疾病活动评分 (DAS28) 密切相关。在 RA 的早期阶段，单核细胞浸润滑膜组织。然而，SF CCL21 或 CCR7 的阻断阻止了 RA SF 介导的单核细胞迁移。新迁移的巨噬细胞中的 CCR7 表达可被 LPS 和 IFNγ 增强，并被 IL-4 处理抑制。我们还发现 CCL21 刺激会增加 M1 极化巨噬细胞 (CD14+CD86+) 的数量，导致 IL-6 和 IL-23 的转录升高。这些 CCL21 诱导的 M1 细胞因子将幼稚 T 细胞分化为 Th17 细胞，而不影响 Th1 细胞极化。在疾病的侵蚀阶段，CCL21 通过 M1 驱动的 Th17 极化增强 RA 破骨细胞生成。通过阻断 IL-6、IL-23 或 IL-17 的功能来破坏这种复杂的串扰，会损害 CCL21 的破骨细胞生成能力。与我们的体外研究结果一致，我们确定由 CCL21 介导的关节炎通过将 M1 巨噬细胞的分化与 Th17 细胞联系起来，将关节炎症扩展为骨侵蚀。CCL21 诱导的新血管形成进一步加剧了疾病进展。我们得出结论，CCL21 是 RA 治疗的一个有吸引力的新靶点，