Activation of the STING adaptor attenuates experimental autoimmune encephalitis.
Activation of the STING adaptor attenuates experimental autoimmune encephalitis.
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DOI：
10.4049/jimmunol.1303258
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发表时间：
2014-06-15
期刊：
影响因子：
--
通讯作者：
Mellor AL
中科院分区：
文献类型：
--
作者：
Lemos H;Huang L;Chandler PR;Mohamed E;Souza GR;Li L;Pacholczyk G;Barber GN;Hayakawa Y;Munn DH;Mellor AL
胞质DNA传感激活干扰素基因刺激因子（STING）衔接子以诱导I型干扰素（IFNαβ）产生。诱导持续STING激活的组成型DNA感测引发耐受性破坏，导致自身免疫。在这里，我们表明，DNA纳米颗粒（DNPs）的系统性治疗诱导有效的免疫调节反应，通过STING信号，抑制实验性自身免疫性脑炎（EAE）时，给药后的小鼠与髓鞘少突胶质细胞糖蛋白（MOG）免疫，在EAE发作，或在高峰疾病严重程度。DNP处理减弱效应T细胞向中枢神经系统（CNS）的浸润，并抑制脾脏中对MOG免疫的先天性和适应性免疫应答。在单独用货物DNA或阳离子聚合物处理的小鼠中未观察到治疗反应，表明具有调节功能的细胞的DNP摄取和货物DNA感测对于治疗反应的显现是必需的。完整的STING和IFNαβ受体基因，而不是IFNγ受体基因，是对DNP的治疗反应表现所必需的。用环状二鸟苷酸单磷酸（c-diGMP）激活STING的治疗也延迟了EAE发作并降低了疾病严重程度。对DNP的治疗反应严重依赖于造血细胞中的吲哚胺2，3双加氧酶（IDO）酶活性。因此，DNP和c-diGMP通过经由抑制CNS特异性自身免疫的STING-IFNαβ-IDO途径诱导显性T细胞调节应答来减弱EAE。这些发现揭示了STING-IFNαβ途径在刺激或抑制自身免疫中的二分作用，并将STING活化剂鉴定为一类新型免疫调节药物。
Cytosolic DNA sensing activates the Stimulator of Interferon Genes (STING) adaptor to induce interferon type I (IFNαβ) production. Constitutive DNA sensing to induce sustained STING activation incites tolerance breakdown leading to autoimmunity. Here we show that systemic treatments with DNA nanoparticles (DNPs) induced potent immune regulatory responses via STING signaling that suppressed experimental autoimmune encephalitis (EAE) when administered to mice after immunization with myelin oligodendrocyte glycoprotein (MOG), at EAE onset, or at peak disease severity. DNP treatments attenuated infiltration of effector T cells into the central nervous system (CNS) and suppressed innate and adaptive immune responses to MOG immunization in spleen. Therapeutic responses were not observed in mice treated with cargo DNA or cationic polymers alone, indicating that DNP uptake and cargo DNA sensing by cells with regulatory functions was essential for therapeutic responses to manifest. Intact STING and IFNαβ receptor genes, but not IFNγ receptor genes, were essential for therapeutic responses to DNPs to manifest. Treatments with cyclic diguanylate monophosphate (c-diGMP) to activate STING also delayed EAE onset and reduced disease severity. Therapeutic responses to DNPs were critically dependent on indoleamine 2,3 dioxygenase (IDO) enzyme activity in hematopoietic cells. Thus DNPs and c-diGMP attenuate EAE by inducing dominant T cell regulatory responses via the STING-IFNαβ-IDO pathway that suppress CNS-specific autoimmunity. These findings reveal dichotomous roles for the STING-IFNαβ pathway in either stimulating or suppressing autoimmunity and identify STING activating reagents as a novel class of immune modulatory drugs.
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影响因子：
32.4
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