Silencing c-Rel in macrophages dampens Th1 and Th17 immune responses and alleviates experimental autoimmune encephalomyelitis in mice
Silencing c-Rel in macrophages dampens Th1 and Th17 immune responses and alleviates experimental autoimmune encephalomyelitis in mice
复制标题
沉默巨噬细胞中的 c-Rel 可抑制 Th1 和 Th17 免疫反应，并减轻小鼠实验性自身免疫性脑脊髓炎。
DOI：
10.1038/icb.2017.11
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发表时间：
2017-08-01
影响因子：
4
通讯作者：
Wan, Xiaochun
中科院分区：
文献类型：
--
作者：
Zhang, Hongling;Bi, Jiacheng;Wan, Xiaochun
自身免疫性Th1和Th17反应对实验性自身免疫性脑脊髓炎（EAE）中枢神经系统（CNS）病理的发展至关重要，EAE是人类多发性硬化症的动物模型。尽管巨噬细胞在Th1和Th17反应的发生中起着重要作用，但调节巨噬细胞基因转录是否可以减轻Th1和Th17细胞诱导的中枢神经系统病理尚不清楚。在本研究中，我们通过纳米颗粒递送化学修饰的c-Rel特异性sirna，成功地沉默了EAE小鼠巨噬细胞（包括浸润中枢神经系统的巨噬细胞）中转录因子c-Rel的表达。体外敲低巨噬细胞c-Rel可抑制NF-kappa B靶点的表达，如促炎细胞因子白细胞介素1 β (IL-1 β)和白细胞介素12 (IL-12)/白细胞介素23 （IL-23）的p40，导致共培养EAE小鼠mog特异性T细胞产生干扰素γ (ifn - γ)和白细胞介素17A （IL-17A）的减少。这种作用与EAE小鼠中枢神经系统t细胞浸润减少、临床症状减轻以及致病性Th1和Th17反应下调有关。综上所述，我们的研究结果表明，靶向巨噬细胞中的c-Rel可抑制中枢神经系统特异性Th1和Th17免疫反应，可有效治疗中枢神经系统自身免疫性疾病。
Autoimmune Th1 and Th17 responses are critical for the development of central nervous system (CNS) pathology in experimental autoimmune encephalomyelitis (EAE), an animal model for human multiple sclerosis. Although macrophages play important roles in the development of Th1 and Th17 responses, whether modulating macrophage gene transcription can diminish the Th1- and Th17 cell-induced CNS pathology is unclear. In this study, we successfully silenced the expression of the transcription factor c-Rel in macrophages of mice with EAE (including those infiltrating the CNS) using chemically modified c-Rel-specific siRNAs delivered by nanoparticles. Knocking down c-Rel in macrophages in vitro inhibited expression of NF-kappa B targets, such as pro-inflammatory cytokines interleukin 1 beta (IL-1 beta) and p40 of interleukin 12 (IL-12)/interleukin 23 (IL-23), in macrophages, leading to reduced interferon gamma (IFN-gamma) and interleukin 17A (IL-17A) production by co-cultured MOG-specific T cells from EAE mice. Such effects correlated with diminished T-cell infiltration in the CNS, reduced clinical symptoms, as well as downregulated pathogenic Th1 and Th17 responses in EAE mice. Taken together, our findings indicate that targeting c-Rel in macrophages dampens CNS-specific Th1 and Th17 immune responses, and can be effective for treating autoimmune diseases of the CNS.