Regulation of Lupus by Cytosolic DNA Sensors

细胞质 DNA 传感器对狼疮的调节

• 批准号: 9229764
• 负责人: Katherine A. Fitzgerald
• 金额: $ 53.56万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-10 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9229764
• 关键词: Adverse effects; Alleles; American; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Antibody Complex; Autoantibodies; Autoimmune Process; Autoimmunity; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Bacterial Infections; Biological Response Modifiers; Bone Marrow; CRISPR/Cas technology; Cell Lineage; Cells; Chimera organism; Chronic; Chronic Disease; Clinical; Complex; Cytosol; DNA; DNA Virus Infections; Dangerousness; Data; Dendritic Cells; Deoxyribonucleases; Development; Dinucleoside Phosphates; Dioxygenases; Disease; Enzymes; Family; Future; Genetic Transcription; Hematopoietic; Host Defense; Immune; Immunity; Immunosuppressive Agents; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Interferon Type I; Interferons; Intuition; Ligands; Longevity; Lupus; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Mutation; Myelogenous; Myeloid Cells; Nucleic Acids; Outcome; PTPRC gene; Pathogenesis; Pathogenicity; Pathway interactions; Pattern recognition receptor; Periodicity; Phenotype; Play; Pristane; Process; Production; Proteins; Pyrroles; Radiation Chimera; Receptor Activation; Receptor Cell; Regimen; Regulation; Role; Signal Transduction; Systemic Lupus Erythematosus; TLR3 gene; TREX1 gene; Testing; Therapeutic; Toll-like receptors; Transferase; Work; autoinflammatory; cell type; cytokine; design; gain of function mutation; human disease; immune activation; immunoregulation; in vivo; indoleamine; inducible gene expression; inhibitor/antagonist; insight; macromolecule; macrophage; member; microbial; microbiome; mouse model; neutrophil; novel; nuclease; pathogen; prevent; programs; pseudotoxoplasmosis syndrome; public health relevance; receptor; response; sensor; small molecule inhibitor; systemic autoimmune disease; targeted treatment; transcriptome sequencing

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.

抽象的。 已知胞质和内体 DNA 传感途径在宿主防御中发挥着关键作用 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 促进自身免疫和自身炎症疾病的发生和进展。例如，内体 TLRs 有助于系统性红斑狼疮 (SLE) 的发病机制，部分是通过促进 I 型干扰素的生产。细胞质 DNA 可以被多种受体检测到，包括 cGAS，它在 转生成一种不寻常的环状二核苷酸，可激活 STING 下游的通路。过度激活 STING 的发生，无论是核酸酶活性丧失还是 STING 功能获得突变，也会驱动强 I 型 干扰素反应现在与艾卡迪-古蒂埃综合征等疾病有关。我们已经探索了 小鼠 SLE 中细胞质和内体传感器之间的潜在串扰。出乎意料的是，我们发现 缺乏 STING 的易患 SLE 的小鼠会出现更严重的临床疾病，而不是较不严重的疾病。这些观察者—— 变化表明 STING 在 TLR 驱动的系统性自身免疫的负调节中发挥新作用。我们的 初步研究使我们提出，血液中 STING 通路的组成型激活 造血细胞限制骨髓细胞对 TLR 配体的炎症反应，促进生成 免疫激活负调节因子（例如 A20）和免疫调节酶（例如 吲哚胺吡咯 2,3-双加氧酶 (IDO)，有助于 B 细胞耐受诱导；核苷酸基 转移酶 DNA 传感器 cGAS 作用于上游以识别宿主 DNA 并调节这些 STING 介导的 影响。我们将通过以下具体目标来验证和探索这一假设：（1）识别细胞 由于 STING 缺陷而直接激活的类型； (2) 探讨其分子机制 STING 介导的 TLR 驱动炎症抑制； (3) 确定 cGAS 在负面影响中的作用 STING 的监管作用。为了精确比较 STING 充足和 STING 缺乏的巨噬细胞，树突状细胞 SLE 模型中的细胞和 B 细胞，我们将利用自身免疫倾向的 CD45 和 Igh 等位基因不同的混合 骨髓嵌合体。该策略将排除亚临床引起的任何潜在混杂因素 感染、微生物组的变化或疾病驱动的炎症的影响。 SLE是一种复杂的慢性系统性疾病 自身免疫性疾病困扰着超过 150 万美国人。目前的治疗方法包括免疫抑制 与使人衰弱的不良副作用相关的治疗方案。尝试开发安全有效的疗法 已知抑制剂的体内半衰期相对较短，并且阻碍了 TLR 的激活 完全封锁 MyD88 的潜在危险结果。更好地了解自然调节剂 疾病过程将为设计更多针对特定疾病的治疗方案提供重要见解 并避免使用可能引发意外危险结果的 STING 拮抗剂。所以， 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。