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（由申请方提供）：脾脏对于清除细胞碎片很重要。这一功能的核心是一组专门的巨噬细胞，它们识别并捕获循环中的颗粒物质。在系统性红斑狼疮中，巨噬细胞清除亲爱细胞的功能缺陷促进了疾病的发展和进展。然而，这在功能层面上是如何发生的尚不清楚。为了检验这一点，我们从自发发展狼疮样疾病的小鼠的脾脏中取出巨噬细胞，发现这种自身免疫性大大增加，表明脾脏巨噬细胞在预防全身性自身免疫性中起重要作用。我们随后发现，死亡细胞诱导一种酶的表达，这种酶降解必需氨基酸色氨酸，是重要的免疫耐受。此外，我们发现阻断这种酶，吲哚胺2-3双加氧酶，极大地改变了巨噬细胞对死细胞的反应方式，并导致狼疮易感动物自身免疫性疾病活动增加。这些数据强烈表明，这种活动可能是重要的预防免疫反应的自我决定因素在一个新的监管机制。我们的项目将研究死亡细胞如何诱导吲哚胺2-3双加氧酶（IDO）的表达，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。该项目的研究结果可能对慢性炎症性疾病的治疗产生巨大影响，提供对基础生物学和新治疗靶点的更好理解。