Mechanisms of marginal zone macrophage mediated tolerance towards apoptotic cell

描述(申请人提供)：脾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，它们识别和捕获循环中的颗粒物质。在系统性红斑狼疮中，巨噬细胞清除亲本细胞的功能缺陷促进了疾病的发生和发展。然而，这是如何在功能层面上发生的尚不清楚。为了研究这一点，我们从自发发展成狼疮样疾病的小鼠的脾中取出巨噬细胞，发现这极大地增强了自身免疫，这意味着脾巨噬细胞在防止全身自身免疫方面发挥着重要作用。我们随后发现，死亡细胞诱导一种酶的表达，该酶降解必需的氨基酸色氨酸，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亡细胞的反应方式，并导致狼疮易发动物的自身免疫性疾病活动增加。这些数据有力地表明，这种活性可能在预防免疫反应中的自我决定因素在新的调节机制中发挥重要作用。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，该酶的表达如何影响凋亡细胞介导的耐受，以及IDO可能影响淋巴细胞和树突状细胞行为的机制。该项目的发现可能会对慢性炎症性疾病的治疗产生巨大的影响，提供对基础生物学的更多了解以及新的治疗靶点。

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.