Regulation of Lupus by Cytosolic DNA Sensors

抽象的。 胞液和胞体DNA传感通路在寄主防御中发挥关键作用。 微生物病原体。相同的模式识别受体也检测内源性配体，从而 促进自身免疫性和自体炎性疾病的发生和发展。例如，内吞体 TLRs参与系统性红斑狼疮(SLE)的发病机制，部分是通过促进 I型IFN的生产。胞浆DNA可以被多种受体检测到，包括cGAS，它在 TURN会产生一种不寻常的环二核苷酸，激活STING下游的通路。过度激活 由于核酸酶活性丧失或STING功能获得突变而导致的STING，也会导致强I型 干扰素反应现在与艾卡迪-古铁雷斯综合征等疾病有关。我们已经探索了 小鼠系统性红斑狼疮胞液和胞体感应器之间的潜在串扰。出乎意料的是，我们发现 有刺痛缺陷的易患系统性红斑狼疮的小鼠的临床疾病更严重，而不是更轻。这些观察者- 研究表明，在TLR驱动的系统自身免疫的负性调节中，STING具有新的作用。我们的 初步的研究表明，血液中刺痛通路的结构性激活可能是一种致病机制。 脂肪细胞限制髓系细胞对TLR配体的炎症反应，促进TLR的产生 免疫激活的负面调节因子，如A20和免疫调节酶，如 吲哚-吡咯-2，3-双加氧酶(IDO)，并有助于诱导B细胞耐受；核苷酸 转移酶DNA传感器cGAS在上游作用，识别宿主DNA并调节这些刺突介导的 效果。我们将通过以下具体目标来验证和探索这一假设：(1)鉴定细胞 刺缺乏直接激活的类型；(2)探讨其分子机制 STING介导的抑制TLR驱动的炎症；以及(3)确定cGAS在阴性中的作用 刺痛的调节作用。为了精确比较刺充足和刺不足的巨噬细胞，树突状细胞 在SLE模型中，我们将利用自身免疫倾向的CD45和IgH等位基因截然不同的混合 骨髓嵌合体。这一策略将排除亚临床引起的任何潜在的混杂因素 感染，微生物群的变化，或疾病引起的炎症的影响。系统性红斑狼疮是一种复杂的慢性系统性疾病。 折磨着150多万美国人的自身免疫性疾病。目前的治疗方法包括免疫抑制。 与衰弱的不良副作用相关的治疗方案。试图开发安全有效的治疗方法 阻断TLR的激活受到已知抑制剂在体内相对较短的半衰期和 完全封锁MyD88的潜在危险后果。更好地了解生物多样性的天然调节因子 疾病过程将为设计更具疾病特异性的治疗方案提供重要的见解 并避免使用可能引发意想不到的危险后果的刺痛拮抗剂。因此， 我们正在探索的机制与人类疾病高度相关，也是未来靶向治疗的关键。

Abstract. Cytosolic and endosomal DNA sensing pathways are known to play a critical role in host defense against microbial pathogens. The same pattern recognition receptors also detect endogenous ligands and thereby promote the onset and progression of autoimmune and autoinflammatory diseases. For example, endosomal TLRs contribute to the pathogenesis of Systemic Lupus Erythematosis (SLE), in part by promoting the production of type I IFNs. Cytosol DNA can be detected by a variety of receptors, including cGAS, which in turn generates an unusual cyclic dinucleotide that activates pathways downstream of STING. Overactivation of STING, either by loss of nuclease activity or STING gain-of-function mutations, also drives a strong type I IFN response now associated with diseases such as Aicardi-Goutieres Syndrome. We have explored the potential crosstalk between cytosolic and endosomal sensors in murine SLE. Quite unexpectedly, we found that STING-deficient SLE-prone mice developed more severe, not less severe, clinical disease. These obser- vations point to a novel role for STING in the negative regulation of TLR-driven systemic autoimmunity. Our preliminary studies have led us to propose that constitutive activation of the STING pathway in hemato- poietic cells limits the inflammatory response of myeloid cells to TLR ligands, promotes the production of negative regulators of immune activation such as A20 and immunomodulatory enzymes such as Indoleamine-pyrrole 2,3-dioxygenase (IDO), and contributes to B cell tolerance induction; the nucleotidyl transferase DNA sensor cGAS acts upstream to recognize host DNA and regulate these STING-mediated effects. We will validate and explore this hypothesis through the following specific aims: (1) identify the cell types directly activated as a result of STING-deficiency; (2) explore the molecular mechanisms responsible for STING-mediated suppression of TLR-driven inflammation; and (3) determine the role of cGAS in the negative regulatory role of STING. To precisely compare STING-sufficient and STING-deficient macrophages, dendritic cells and B cells in models of SLE, we will utilize autoimmune-prone CD45 and Igh allelically distinct mixed bone marrow chimeras.This strategy will preclude any potential confounding factors arising from subclinical infection, changes in microbiome, or effects of disease driven inflammation. SLE is a complex chronic systemic autoimmune disease that afflicts over 1.5 million Americans. Current treatments involve immuno-suppressive regimens associated with debilitating adverse side effects. Attempts to develop safe and efficient therapies that block TLR activation have been stymied by the relative short in vivo half lives of known inhibitors and the potential dangerous outcome of complete MyD88 blockade. Better understanding of the natural regulators of the disease process will provide major insights toward the design of more disease-specific therapeutic options and also avoid the use of STING antagonists that could trigger unanticipated dangerous outcomes. Therefore, the mechanisms we are exploring are highly relevant to human disease and key to future targeted therapies.