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（由应用提供）：从炎症到分辨率的过渡对于损伤或感染后的组织功能的恢复至关重要，组织居民巨噬细胞（TRM）是体内炎症的主动性和分辨率阶段的关键免疫反应器。 TRM通过产生细胞因子来促进炎症，该细胞因子将中性粒细胞（PMN）和其他白细胞募集到损坏的组织中。 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分辨率并恢复到体内稳态。该双重功能是巨噬细胞的定义特性，因此了解触发这些TRM态在炎症期间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率（肿瘤性）可以将巨噬细胞转移到抗炎状态，并且人们认为，巨噬细胞浸润PMN的肿瘤细胞增多症有助于从炎症转向分辨率。然而，体内散发性驱动的分辨率的机制尚不清楚。我们已经发现，产生腺苷的异酶CD73在鼠肺和腹膜TRM上高度表达，腺苷介导的凋亡细胞对巨噬细胞对巨噬细胞对巨噬细胞的抗炎作用对巨噬细胞对体外和体内炎症期间的抗炎作用是必需的。我们的结果揭示了CD73以前未知的和关键作用在控制遗传性吞噬过程中巨噬细胞的炎症反应中。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中的作用在调节TRM中的作用，从体内炎症期间从炎症到分辨率的过渡。在AIM 1中，我们将剖析凋亡细胞在体外依赖CD73依赖性抑制炎性细胞因子的机制。在AIM 2中，我们将确定CD73如何将传染性细胞增多症与肺部和腹膜感染的分辨率联系起来，并研究分子基础，从而使胞吞作用驱动TRM中的促分辨率程序。我们认为，这些研究将对炎症的重要但不理解的方面产生新的机械见解，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害。