Immunoregulatory role of CD73 in efferocytosis

CD73 在胞吞作用中的免疫调节作用

• 批准号: 8962198
• 负责人: Michael Rusty Elliott
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8962198
• 关键词: Acute; Acute Lung Injury; Adenine Nucleotides; Adenosine; Anti-Inflammatory Agents; Anti-inflammatory; Apoptosis; Apoptotic; Biochemical; CCL2 gene; Cells; Chronic; Controlled Study; Data; Dinoprostone; Disease; Elements; Enzymes; Equilibrium; Event; Excision; Feedback; Genetic; Goals; Growth Factor; Health; Homeostasis; Hour; Immune; Immunity; Immunosuppression; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-10; Interleukin-12; Lead; Leukocytes; Life; Link; Lung; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Nucleotides; Pathway interactions; Peritoneal; Peritoneum; Peritonitis; Phagocytosis; Phase; Phenotype; Play; Population; Production; Property; Purinergic P1 Receptors; Recruitment Activity; Regulation; Research Project Grants; Resolution; Role; Series; Signal Pathway; Signal Transduction; TNF gene; Testing; Therapeutic; Tissues; Transforming Growth Factor beta; Vascular Endothelial Growth Factors; Wound Healing; adenosine receptor activation; base; cytokine; functional plasticity; human disease; immune function; immunogenic; in vivo; insight; macrophage; mouse model; neutrophil; novel; novel strategies; prevent; programs; public health relevance; response; restoration

 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(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，而组织驻留巨噬细胞(TRM)是体内炎症启动和消退阶段的关键免疫效应细胞。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，从而促进炎症。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体内平衡的恢复。这种双重功能是巨噬细胞的一个决定性属性，因此了解在炎症过程中触发这些TRM状态的分子和细胞事件具有巨大的治疗前景。巨噬细胞对凋亡细胞的吞噬清除(吞噬作用)可使巨噬细胞进入抗炎状态，而巨噬细胞吞噬PMN的吞噬作用有助于机体从炎症状态向消退状态转变。然而，泡腾作用驱动体内分解的机制还不是很清楚。我们发现，产生腺苷的胞外酶CD73在小鼠肺和腹膜TRM中高表达，在体外和体内炎症过程中，它是腺苷介导的凋亡细胞对巨噬细胞的抗炎作用所必需的。我们的结果揭示了CD73在巨噬细胞吞噬过程中控制炎症反应的一个先前未知的关键作用。在此，我们建议确定凋亡细胞在巨噬细胞中诱导CD73依赖的抗炎程序的机制，并研究CD73在体内炎症过程中TRM上CD73在调节炎症向消退转变中的作用。在目标1中，我们将在体外剖析CD73依赖的凋亡细胞抑制炎性细胞因子产生的机制。在目标2中，我们将确定CD73如何将胞吐作用与肺部和腹膜炎症的消退联系起来，并研究胞吐作用在TRM中驱动促消解程序的分子基础。我们相信，这些研究将对炎症的一个重要但鲜为人知的方面产生新的机制见解，这将有助于开发新的方法来研究和控制急性和慢性炎症性疾病期间的组织损伤。