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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：
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
项目类别：
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

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.