Immunoregulatory role of CD73 in efferocytosis

CD73 在胞吞作用中的免疫调节作用

• 批准号: 9054775
• 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/9054775
• 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; Health; Homeostasis; Hour; Immune; Immunity; Immunosuppression; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-1 beta; 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; 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（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器。 TRM 通过产生细胞因子来招募中性粒细胞 (PMN) 和其他白细胞进入受损组织，从而促进炎症。 TRM 还通过清除凋亡细胞浸润并产生抗炎细胞因子和生长因子来促进炎症消退并恢复体内平衡。这种双重功能是巨噬细胞的一个决定性特性，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巨大的治疗前景。已知凋亡细胞的吞噬清除作用（胞吞作用）可将巨噬细胞转变为抗炎状态，并且认为巨噬细胞浸润中性粒细胞的胞吞作用有助于从炎症到体内消退的转变。然而，体内胞吞作用驱动的分辨率机制尚不清楚。我们发现，产生腺苷的胞外酶 CD73 在小鼠肺和腹膜 TRM 上高表达，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。我们的结果揭示了 CD73 在胞吞作用过程中控制巨噬细胞炎症反应中的先前未知的关键作用。在这里，我们建议定义凋亡细胞在巨噬细胞中诱导CD73依赖性抗炎程序的机制，并研究CD73在TRM上在调节体内炎症从炎症到消退的转变中的作用。在目标 1 中，我们将剖析体外凋亡细胞依赖 CD73 抑制炎症细胞因子产生的机制。在目标 2 中，我们将确定 CD73 如何将胞吞作用与肺部和腹膜炎症的消退联系起来，并研究胞吞作用驱动 TRM 中促消退程序的分子基础。我们相信这些研究将对炎症的一个重要但知之甚少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。