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。 已知胞质和内体DNA传感途径在宿主防御中起关键作用， 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身炎症性疾病的发生和发展。例如，内体 TLR参与系统性红斑狼疮（SLE）的发病机制，部分是通过促进 生产I型IFN。细胞溶胶DNA可以通过多种受体检测，包括cGAS，其在细胞内表达。 turn产生一种不寻常的环状二核苷酸，激活STING下游的途径。过度激活 无论是通过核酸酶活性的丧失还是STING功能获得性突变， 干扰素反应现在与疾病如Aicardi-Goutieres综合征有关。我们已经探索了 在小鼠SLE中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 STING缺陷型SLE易感小鼠的临床疾病更严重，而不是更轻。这些观察者- 研究结果指出STING在TLR驱动的系统性自身免疫的负调节中的新作用。我们 初步的研究使我们提出，STING途径在血细胞中的组成性激活， 造血细胞限制了骨髓细胞对TLR配体的炎症反应，促进了TLR配体的产生， 免疫激活的负调节因子如A20和免疫调节酶如 吲哚胺-吡咯2，3-双加氧酶（IDO），并有助于B细胞耐受性诱导; 转移酶DNA传感器cGAS在上游识别宿主DNA并调节这些STING介导的 方面的影响.我们将通过以下具体目标验证和探索这一假设：（1）识别细胞 由于STING缺乏而直接激活的类型;（2）探索负责的分子机制 STING介导的TLR驱动的炎症抑制;和（3）确定cGAS在负性炎症中的作用。 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 细胞和B细胞在SLE模型中，我们将利用自身免疫倾向的CD 45和Igh等位基因不同的混合物， 这种策略将排除亚临床嵌合体引起的任何潜在的混杂因素。 感染、微生物组的变化或疾病驱动的炎症的影响。SLE是一种复杂的慢性全身性疾病， 自身免疫性疾病折磨着超过150万美国人。目前的治疗包括免疫抑制 与使人衰弱的不良副作用相关的方案。尝试开发安全有效的治疗方法， 阻断TLR活化受到已知抑制剂的相对短的体内半衰期的阻碍， MyD 88完全阻断的潜在危险结局。更好地了解天然调节剂， 疾病的过程将为设计更多的疾病特异性治疗方案提供重要的见解 并避免使用可能引发意外危险结果的STING拮抗剂。因此，我们认为， 我们正在探索的机制与人类疾病高度相关，是未来靶向治疗的关键。