Mechanistic relationships between IDO, GCN2, and mTOR signals in immunity to apoptotic cells

IDO、GCN2 和 mTOR 信号在凋亡细胞免疫中的机制关系

• 批准号: 9268408
• 负责人: Tracy L McGaha
• 金额: $ 23.76万
• 依托单位: UNIVERSITY HEALTH NETWORK
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9268408
• 关键词: Amino Acids; Animals; Antigens; Apoptotic; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; Blood Circulation; Cell Death; Cells; Characteristics; Clinical; Consumption; Data; Defect; Dendritic Cells; Dioxygenases; Disease; Disease Progression; Enzymes; Experimental Models; FRAP1 gene; Functional disorder; Generations; Homeostasis; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Individual; Inflammation; Inflammatory; Interleukin-10; Interleukin-12; Interleukin-6; Interruption; Lead; Link; Lupus; Malignant Neoplasms; Mediating; Metabolic stress; Molecular; Natural Immunity; Nuclear Antigens; Nutritional; Organ; Pathogenesis; Pathway interactions; Peripheral; Pharmacology; Phosphotransferases; Play; Process; Production; Recruitment Activity; Regulation; Regulatory Pathway; Regulatory T-Lymphocyte; Role; Signal Pathway; Signal Transduction; Spleen; Splenic Red Pulp; Stress; System; Systemic Lupus Erythematosus; Testing; Therapeutic; Time; Tryptophan; Tryptophan Metabolism Pathway; adaptive immunity; autocrine; biological adaptation to stress; blood filter; immunogenic; indoleamine; mTOR inhibition; macrophage; novel; public health relevance; response; sensor; systemic autoimmune disease

 DESCRIPTION (provided by applicant): The spleen is required for the generation of systemic tolerance to apoptotic cells. We have recently shown a specialized set of macrophages residing in the marginal zone region of the red pulp drive immunologic tolerance to apoptotic material and in their absence apoptotic cells induce inflammation and autoimmune reactivity. While it is not known how this occurs on a mechanistic level, we have found apoptotic cells provoke expression of a tryptophan-catabolizing enzyme, indoleamine 2, 3 dioxygenase (IDO), which is critical for immune suppression in a variety of inflammatory settings. Further we discovered blockade of IDO greatly altered the way macrophages and dendritic cells respond to apoptotic cells with increased inflammatory immunity and autoimmune disease activity in lupus-prone animals. Thus the data suggest a novel mechanism whereby IDO activity in macrophages controls both innate and adaptive immunity to apoptotic cells. Our proposed project will examine how apoptotic cells driven IDO activity impacts mTOR signals in marginal zone macrophages, how IDO-driven tryptophan metabolism impacts apoptotic cell-mediated tolerance, and mechanisms by which IDO may influence Treg activation; finally testing these mechanisms in an experimental model of systemic lupus erythematosus. Thus, the findings of this project could have enormous implications in diseases of hypo and hyper-immunity where modulation of the tolerogenic rheostat would provide significant clinical benefit.

 描述（由申请人提供）：脾脏是产生对凋亡细胞的全身耐受性所必需的。我们最近发现，存在于红髓边缘区的一组专门的巨噬细胞驱动对凋亡物质的免疫耐受，并且在它们不存在的情况下，凋亡细胞会诱导炎症和自身免疫反应性。虽然尚不清楚这是如何在机制水平上发生的，但我们发现凋亡细胞会引发色氨酸分解酶、吲哚胺 2, 3 双加氧酶 (IDO) 的表达，这对于各种炎症环境中的免疫抑制至关重要。此外，我们发现 IDO 的阻断极大地改变了巨噬细胞和树突状细胞对凋亡细胞的反应方式，增加了易患狼疮的动物的炎症免疫和自身免疫性疾病活动。因此，这些数据表明了一种新的机制，巨噬细胞中的 IDO 活性可以控制对凋亡细胞的先天免疫和适应性免疫。我们提出的项目将研究凋亡细胞驱动的 IDO 活性如何影响边缘区巨噬细胞中的 mTOR 信号，IDO 驱动的色氨酸代谢如何影响凋亡细胞介导的耐受性，以及 IDO 影响 Treg 激活的机制；最后在系统性红斑狼疮实验模型中测试这些机制。因此，该项目的研究结果可能对免疫低下和免疫过度疾病产生巨大影响，其中耐受性变阻器的调节将提供显着的临床益处。