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Immunoregulatory role of CD73 in efferocytosis

CD73 在胞吞作用中的免疫调节作用

基本信息

批准号：
10051439
负责人：
Michael Rusty Elliott
金额：
$ 6.47万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-15 至 2021-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10051439
关键词：
Immunoregulatory role CD73 efferocytosis

项目摘要

DESCRIPTION (provided by applicant): The transition from inflammation to resolution is critical for the restoration of tissue function following injury or infection, and tissue resident macrophages (TRM) are key immune effectors of both the initiation and resolution phases of inflammation in vivo. TRM promote inflammation by producing cytokines that recruit neutrophils (PMN) and other leukocytes into the damaged tissue. TRM also promote the resolution of inflammation and return to homeostasis by clearing apoptotic cell infiltrates and by producing anti-inflammatory cytokines and growth factors. This dual functionality is a defining property of macrophages, and thus understanding the molecular and cellular events that trigger these TRM states during inflammation holds great therapeutic promise. The phagocytic clearance of apoptotic cells (efferocytosis) is known to shift macrophages toward an anti-inflammatory state, and it is thought that the efferocytosis of infiltrating PMN by macrophages contributes to the shif from inflammation to resolution vivo. However, the mechanisms of efferocytosis-driven resolution in vivo are not well understood. We have found that the adenosine-generating ecto-enzyme CD73 is highly expressed on murine lung and peritoneal TRM and that it is required for the adenosine-mediated anti- inflammatory effects of apoptotic cells on macrophages in vitro and during inflammation in vivo. Our results reveal a previously unknown and critical role for CD73 in controlling inflammatory responses of macrophages during efferocytosis. Here we propose to define the mechanisms whereby apoptotic cells induce a CD73- dependent anti-inflammatory program in macrophages and to investigate the role of CD73 on TRM in regulating the transition from inflammation to resolution during inflammation in vivo. In Aim 1 we will dissect the mechanisms of CD73-dependent suppression of inflammatory cytokine production by apoptotic cells in vitro. In Aim 2, we will determine how CD73 links efferocytosis to the resolution of pulmonary and peritoneal inflammation and investigate the molecular basis whereby efferocytosis drives a pro-resolution program in TRM. We believe these studies will produce novel mechanistic insights into an important but poorly understood aspect of inflammation that will aid in developing new approaches to study and control tissue damage during acute and chronic inflammatory diseases.

描述（由申请人提供）：从炎症到消退的转变对于损伤或感染后组织功能的恢复至关重要，组织驻留巨噬细胞（TRM）是体内炎症起始和消退阶段的关键免疫效应物。TRM通过产生细胞因子将中性粒细胞（PMN）和其他白细胞招募到受损组织中来促进炎症。TRM还通过清除凋亡细胞浸润和产生抗炎细胞因子和生长因子来促进炎症的消退和恢复稳态。这种双重功能是巨噬细胞的一种定义性质，因此了解炎症期间触发这些TRM状态的分子和细胞事件具有很大的治疗前景。已知凋亡细胞的吞噬清除（吞噬作用）使巨噬细胞向抗炎状态转变，并且认为巨噬细胞对浸润性PMN的吞噬作用有助于从炎症向体内消退的转变。然而，体内巨噬细胞增殖驱动的消退机制还不清楚。我们已经发现，产生腺苷的胞外酶CD73在鼠肺和腹膜TRM上高度表达，并且它是体外和体内炎症期间凋亡细胞对巨噬细胞的腺苷介导的抗炎作用所必需的。我们的研究结果揭示了一个以前未知的和关键的作用，CD73在控制炎症反应的巨噬细胞在巨噬细胞。在这里，我们建议定义的机制，凋亡细胞诱导的CD73依赖性的抗炎程序在巨噬细胞和研究的作用，CD73对TRM在调节从炎症到解决在体内炎症过程中的过渡。在目标1中，我们将剖析CD73依赖性抑制体外凋亡细胞产生炎性细胞因子的机制。在目标2中，我们将确定CD73如何将红细胞增多症与肺部和腹膜炎症的消退联系起来，并研究红细胞增多症驱动TRM中促消退程序的分子基础。我们相信，这些研究将产生新的机制见解的一个重要的，但了解甚少的方面，炎症，这将有助于开发新的方法来研究和控制组织损伤在急性和慢性炎症性疾病。