Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912;
Cancer Immunology, Inflammation and Tolerance Program, Cancer Center, Georgia Regents University, Augusta, GA 30912; Department of Pharmacology, School of Medicine of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP 14049-900 Sao Paulo, Brazil;
J Immunol. 2014 Jun 15;192(12):5571-8. doi: 10.4049/jimmunol.1303258. Epub 2014 May 5.
Cytosolic DNA sensing activates the stimulator of IFN genes (STING) adaptor to induce IFN type I (IFN-αβ) production. Constitutive DNA sensing to induce sustained STING activation incites tolerance breakdown, leading to autoimmunity. In this study, 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 CNS and suppressed innate and adaptive immune responses to myelin oligodendrocyte glycoprotein 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 IFN-αβ receptor genes, but not IFN-γ receptor genes, were essential for therapeutic responses to DNPs to manifest. Treatments with cyclic diguanylate monophosphate to activate STING also delayed EAE onset and reduced disease severity. Therapeutic responses to DNPs were critically dependent on IDO enzyme activity in hematopoietic cells. Thus, DNPs and cyclic diguanylate monophosphate attenuate EAE by inducing dominant T cell regulatory responses via the STING/IFN-αβ/IDO pathway that suppress CNS-specific autoimmunity. These findings reveal dichotomous roles for the STING/IFN-αβ pathway in either stimulating or suppressing autoimmunity and identify STING-activating reagents as a novel class of immune modulatory drugs.
细胞质 DNA 感应激活干扰素基因刺激物 (STING) 衔接蛋白，诱导 I 型干扰素 (IFN-αβ) 的产生。持续的 DNA 感应诱导持续的 STING 激活会引发耐受崩溃，导致自身免疫。在这项研究中，我们表明，通过 STING 信号系统地用 DNA 纳米颗粒 (DNP) 处理可以诱导强烈的免疫调节反应，当在髓鞘少突胶质细胞糖蛋白 (MOG) 免疫后给小鼠施用、在 EAE 发病时或疾病严重程度峰值时施用时，可抑制实验性自身免疫性脑脊髓炎 (EAE)。DNP 处理可减弱效应 T 细胞向中枢神经系统的浸润，并抑制脾脏中对髓鞘少突胶质细胞糖蛋白免疫的先天和适应性免疫反应。在用 cargo DNA 或阳离子聚合物单独处理的小鼠中未观察到治疗反应，表明 DNP 的摄取和具有调节功能的细胞对 cargo DNA 的感应对于治疗反应的显现是必需的。完整的 STING 和 IFN-αβ 受体基因，但不是 IFN-γ 受体基因，对于 DNP 治疗反应的显现是必需的。用环二鸟苷酸单磷酸 (cyclic diguanylate monophosphate) 激活 STING 也可延迟 EAE 发病并降低疾病严重程度。DNP 的治疗反应在很大程度上取决于造血细胞中 IDO 酶的活性。因此，DNP 和环二鸟苷酸单磷酸通过 STING/IFN-αβ/IDO 途径诱导显性 T 细胞调节反应，抑制中枢神经系统特异性自身免疫，从而减轻 EAE。这些发现揭示了 STING/IFN-αβ 途径在刺激或抑制自身免疫中的双重作用，并确定 STING 激活试剂为一类新的免疫调节药物。
