The parasitic helminth product ES-62 suppresses pathogenesis in collagen-induced arthritis by targeting the interleukin-17-producing cellular network at multiple sites
The parasitic helminth product ES-62 suppresses pathogenesis in collagen-induced arthritis by targeting the interleukin-17-producing cellular network at multiple sites
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DOI：
10.1002/art.34581
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发表时间：
2012-10-01
影响因子：
--
通讯作者：
Harnett, Margaret M.
中科院分区：
文献类型：
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作者：
Pineda, Miguel A.;McGrath, Mairi A.;Harnett, Margaret M.
目的在众多的生存策略中，寄生蠕虫分泌调节宿主免疫反应的分子。一种这样的产品，ES-62，是保护免受胶原诱导的关节炎（CIA），类风湿性关节炎（RA）的模型。由于白细胞介素-17（IL-17）已被报道在RA的发展中发挥致病作用，因此本研究旨在研究IL-17的靶向作用是否可以解释ES-62提供的对CIA的保护。方法DBA/1小鼠经II型胶原免疫后逐渐出现关节炎。ES-62的保护作用通过测定细胞因子水平、相关细胞群的流式细胞术分析和CIA小鼠关节炎症的原位分析来评估。结果ES-62可下调CIA小鼠的IL-17反应。首先，它通过靶向一个复杂的IL-17产生网络来抑制IL-17应答的启动和极化，该网络涉及树突状细胞和？d或CD 4 + T细胞。此外，ES-62通过下调髓样分化因子88的表达来直接靶向Th 17细胞，从而抑制由IL-1和Toll样受体配体介导的应答。此外，ES-62调节？/ d T细胞，这反映了直接抑制CD 44的上调，并证明了原位分析，大大降低了IL-17产生细胞的水平，包括淋巴细胞，浸润关节。最后，存在对驻留在关节中的细胞（例如骨区域内的破骨细胞）产生的IL-17的强烈抑制。结论ES-62治疗CIA小鼠可对IL-17炎症网络的起始期和效应期进行独特的多位点调控。ES-62可用于开发RA的新疗法。
Objective Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid arthritis (RA). Since interleukin-17 (IL-17) has been reported to play a pathogenic role in the development of RA, this study was undertaken to investigate whether targeting of IL-17 may explain the protection against CIA afforded by ES-62. Methods DBA/1 mice progressively display arthritis following immunization with type II collagen. The protective effects of ES-62 were assessed by determination of cytokine levels, flow cytometric analysis of relevant cell populations, and in situ analysis of joint inflammation in mice with CIA. Results ES-62 was found to down-regulate IL-17 responses in mice with CIA. First, it acted to inhibit priming and polarization of IL-17 responses by targeting a complex IL-17producing network, involving signaling between dendritic cells and ?/d or CD4+ T cells. In addition, ES-62 directly targeted Th17 cells by down-regulating myeloid differentiation factor 88 expression to suppress responses mediated by IL-1 and Toll-like receptor ligands. Moreover, ES-62 modulated the migration of ?/d T cells and this was reflected by direct suppression of CD44 up-regulation and, as evidenced by in situ analysis, dramatically reduced levels of IL-17producing cells, including lymphocytes, infiltrating the joint. Finally, there was strong suppression of IL-17 production by cells resident in the joint, such as osteoclasts within the bone areas. Conclusion Our findings indicate that ES-62 treatment of mice with CIA leads to unique multisite manipulation of the initiation and effector phases of the IL-17 inflammatory network. ES-62 could be exploited in the development of novel therapeutics for RA.