Promotion of the Local Differentiation of Murine Th17 Cells by Synovial Macrophages During Acute Inflammatory Arthritis
Promotion of the Local Differentiation of Murine Th17 Cells by Synovial Macrophages During Acute Inflammatory Arthritis
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DOI：
10.1002/art.24075
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发表时间：
2008-12-01
影响因子：
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通讯作者：
Wicks, Ian P.
中科院分区：
文献类型：
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作者：
Egan, Paul J.;van Nieuwenhuijze, Annemarie;Wicks, Ian P.
目标。采用白细胞介素-17 （il -17）依赖的急性炎性关节炎模型，观察组织炎症部位和引流淋巴结中促炎Th17细胞的产生。通过在膝关节关节内注射甲基化牛血清白蛋白（mBSA）和皮下注射IL-1 β诱导小鼠关节炎。在关节炎诱导期间给予抗il -17或对照抗体。细胞因子的表达通过滑膜淋巴细胞的细胞内细胞因子染色、淋巴结细胞提取RNA的聚合酶链反应分析和细胞培养上清的酶联免疫吸附测定来评估。在与关节炎小鼠巨噬细胞共培养的情况下，观察初始CD4+ T细胞的Th17分化情况。在急性关节炎期间给予抗IL-17抗体明显减少疾病，表明该模型依赖IL-17。在引流淋巴结CD4+ T细胞中检测到IL-17信使RNA (mRNA)，而非蛋白质，并在关节炎症发生前检测到。此外，注射mBSA和IL-1 β后，在淋巴结中检测到Th17细胞刺激因子（转化生长因子β， IL-6）和Th17细胞抑制因子（干扰素γ， IL-4）的mRNA。在疾病的高峰期，在炎症滑膜中清晰地发现了Th17细胞。滑膜巨噬细胞支持由CD3刺激的幼稚CD4+ T细胞前体生成Th17细胞，并产生高水平的IL-6。相比之下，腹腔巨噬细胞不能诱导Th17细胞分化，产生较少的il -6。这些结果表明，Th17细胞分化始于引流淋巴结，但产生il -17的细胞仅限于炎症滑膜，是在炎性巨噬细胞产生的局部细胞因子的反应下产生的。
Objective. To examine the generation of proinflammatory Th17 cells at the site of tissue inflammation and in draining lymph nodes using an interleukin-17 (IL17)-dependent model of acute inflammatory arthritis.Methods. Arthritis was elicited in mice by intra-articular injection of methylated bovine serum albumin (mBSA) into the knee and subcutaneous injection of IL-1 beta. Anti-IL-17 or control antibodies were administered during arthritis induction. Cytokine expression was evaluated by intracellular cytokine staining of synovial lymphocytes, by polymerase chain reaction analysis of RNA extracted from lymph node cells, and by enzyme-linked immunosorbent assay of cell culture supernatants. Th17 differentiation of naive CD4+ T cells was assessed in cocultures with macrophages from arthritic mice.Results. Anti-IL-17 antibody administered during acute arthritis markedly reduced disease, indicating that the model is IL-17 dependent. IL-17 messenger RNA (mRNA), but not protein, was detected in draining lymph node CD4+ T cells and preceded joint inflammation. In addition, mRNA for Th17 cell-stimulatory cytokines (transforming growth factor beta, IL-6) and Th17 cell-inhibitory cytokines (interferon-gamma, IL-4) was detected in lymph nodes following injection of mBSA and IL-1 beta. Th17 cells were clearly identified in the inflamed synovium at the peak of disease. Synovial macrophages supported Th17 cell generation from naive CD4+ T cell precursors stimulated via CD3 in vitro and produced high levels of IL-6. In contrast, peritoneal macrophages failed to induce Th17 cell differentiation and produced less IL-6.Conclusion. These results suggest that Th17 cell differentiation is initiated in draining lymph nodes but that IL-17-producing cells are restricted to the inflamed synovium, being generated in response to local cytokines produced by inflammatory macrophages.