CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis.
CCL21/CCR7 signaling in macrophages promotes joint inflammation and Th17-mediated osteoclast formation in rheumatoid arthritis.
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巨噬细胞中的CCL21/CCR7信号传导促进了类风湿关节炎中的关节炎症和Th17介导的破骨细胞形成。
DOI：
10.1007/s00018-019-03235-w
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发表时间：
2020-04
期刊：
影响因子：
--
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中科院分区：
文献类型：
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在类风湿关节炎(RA)中，滑膜组织中大量表达CCL21，这是一种与RA易感性密切相关的趋化因子。本研究旨在探讨CCL21/CCR7信号在类风湿关节炎发病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早期，单核细胞渗入滑膜组织。然而，阻断SF CCL21或CCR7可阻止RA SF介导的单核细胞迁移。新迁移的巨噬细胞CCR7的表达可被脂多糖和干扰素γ增强，而被IL-4抑制。我们还发现，CCL21刺激增加了M1极化的巨噬细胞(CD14+CD86+)的数量，导致IL-6和IL-23转录增加。这些CCL21诱导的M1细胞因子将原始T细胞分化为Th17细胞，而不影响Th1细胞的极化。在疾病的侵蚀性阶段，CCL21通过M1驱动的Th17极化促进RA破骨细胞的形成。通过阻断IL-6、IL-23或IL-17的功能，干扰这种复杂的串扰，会削弱CCL21的破骨细胞形成能力。与我们的体外研究结果一致，我们证实，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，将关节炎症扩大到骨侵蚀。CCL21诱导的新生血管进一步加剧了疾病的进展。我们得出结论，CCL21是RA治疗的一个有吸引力的新靶点，因为阻断其功能可能会消除M1巨噬细胞和Th17细胞串扰调节的侵蚀性关节炎。
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.
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DOI：
10.4049/jimmunol.1800348
发表时间：
2018-07-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Cosway EJ;Ohigashi I;Schauble K;Parnell SM;Jenkinson WE;Luther S;Takahama Y;Anderson G
通讯作者：
Anderson G
影响因子：
4.4
作者：
Otero, Carolina;Groettrup, Marcus;Legler, Daniel F.
通讯作者：
Legler, Daniel F.
影响因子：
--
作者：
Pickens, Sarah R.;Chamberlain, Nathan D.;Volin, Michael V.;Mandelin, Arthur M., II;Agrawal, Hemant;Matsui, Masanori;Yoshimoto, Takayuki;Shahrara, Shiva
通讯作者：
Shahrara, Shiva
影响因子：
6
作者：
Kim, Kyoung-Woon;Kim, Hae-Rim;Lee, Sang-Heon
通讯作者：
Lee, Sang-Heon
影响因子：
8.8
作者：
Revu S;Wu J;Henkel M;Rittenhouse N;Menk A;Delgoffe GM;Poholek AC;McGeachy MJ
通讯作者：
McGeachy MJ