Mechanisms of marginal zone macrophage mediated tolerance towards apoptotic cell

边缘区巨噬细胞介导的凋亡细胞耐受机制

• 批准号: 8716373
• 负责人: Tracy L McGaha
• 金额: $ 35.25万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716373
• 关键词: Ablation; Animals; Antigens; Apoptotic; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biology; Blood Circulation; CD8B1 gene; Cells; Chronic; Data; Dendritic Cells; Development; Dioxygenases; Disease; Enzymes; Essential Amino Acids; Immune Tolerance; Immune response; Immunity; Immunosuppression; Inflammation; Inflammatory; Inflammatory Response; Interleukin-12; Interleukin-6; Kinetics; Kynurenine; Laboratories; Lead; Lupus; Lymphocyte; Mediating; Mus; Particulate Matter; Phagocytes; Phagocytosis; Phenotype; Phosphotransferases; Play; Prevention; Process; Production; Regulatory Pathway; Role; SR-A proteins; Self Tolerance; Spleen; Systemic Lupus Erythematosus; T cell response; T-Cell Activation; TNF gene; Testing; Tryptophan; Tryptophan 2,3 Dioxygenase; cell behavior; human FRAP1 protein; in vivo; indoleamine; insight; lupus-like; macrophage; new therapeutic target; novel; prevent; response; stem; trafficking

DESCRIPTION (provided by applicant): The spleen is important for removing cellular debris. Central to this function are a specialized set of macrophages that recognize and capture particulate matter from circulation. In Systemic Lupus Erythematosus it is suggested that defective function of macrophages to clear dear cells promotes disease development and progression. However, how this occurs on a functional level is unknown. To examine this we removed macrophages from the spleen of mice that spontaneously develop lupus-like disease and found this greatly increased autoimmunity signifying splenic macrophages play an important role in preventing systemic autoimmunity. We subsequently found that dead cells induce expression of an enzyme that degrades the essential amino acid tryptophan and is important immune tolerance. Further we found blockade of this enzyme, indoleamine 2-3 dioxygenase, greatly altered the way macrophages respond to dead cells and lead to increased autoimmune disease activity in lupus-prone animals. The data strongly indicate that this activity may be important in the prevention immune responses to self-determinants in a novel regulatory mechanism. Our project will examine how dead cells induce indoleamine 2-3 dioxygenase (IDO) expression, how expression of the enzyme impacts apoptotic cell-mediated tolerance, and mechanisms by which IDO may influence lymphocyte and dendritic cell behavior. The findings of this project could have enormous implications in treatment of chronic inflammatory disease providing greater understanding of the basic biology as well as new therapeutic targets.

描述（由申请人提供）：脾脏对于去除细胞碎片很重要。该功能的核心是一组专门的巨噬细胞，它们从循环中识别并捕获颗粒物。在全身性红斑狼疮中，建议巨噬细胞的缺陷功能清除亲爱的细胞会促进疾病的发育和进展。但是，这种情况如何在功能级别上发生是未知的。为了检查这一点，我们从小鼠的脾脏中去除了巨噬细胞，这些巨噬细胞自发地发展出狼疮样疾病，发现这大大增加了自身免疫性，这表明脾脏巨噬细胞在防止系统性自身免疫方面起着重要作用。随后，我们发现死细胞会诱导降解必需氨基酸色氨酸的酶的表达，并且是重要的免疫耐受性。此外，我们发现了这种酶，吲哚胺2-3二氧酶的阻塞，极大地改变了巨噬细胞对死细胞的反应方式，并导致狼疮易蛋白狼疮动物的自身免疫性疾病活性增加。数据强烈表明，这种活性在新型调节机制中对预防对自决的免疫反应可能很重要。我们的项目将研究死细胞如何诱导吲哚胺2-3二氧酶（IDO）表达，酶的表达如何影响凋亡细胞介导的耐受性以及IDO可能影响淋巴细胞和树突状细胞行为的机制。该项目的发现可能对治疗慢性炎症性疾病具有巨大的影响，从而对基本生物学以及新的治疗靶标有更多的了解。