Regulatory macrophages and the host inflammatory response

调节性巨噬细胞和宿主炎症反应

• 批准号: 8504342
• 负责人: DAVID M MOSSER
• 金额: $ 28.88万
• 依托单位: UNIV OF MARYLAND, COLLEGE PARK
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8504342
• 关键词: Adenosine; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Autoimmune Diseases; Autoimmune Process; B-Lymphocytes; Biochemical; Biochemical Markers; Biological Markers; Cells; Confusion; Disease; Disease Outcome; Disease Progression; Endotoxins; Engineering; Enzymes; Experimental Autoimmune Encephalomyelitis; Exposure to; Goals; Health; Helper-Inducer T-Lymphocyte; Homeostasis; Human; Immune; Immune response; Immunity; Immunosuppressive Agents; In Situ; Inflammation; Inflammatory; Inflammatory Response; Lead; Macrophage Activation; Malignant Neoplasms; Measures; Messenger RNA; Modeling; Molecular; Multiple Sclerosis; Pathology; Phenotype; Physiology; Play; Population; Process; Proteins; Resolution; Role; Severity of illness; Signal Transduction; Stimulus; Surface; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Vaccines; base; immunopathology; improved; macrophage; novel; novel strategies; overexpression; prevent; public health relevance; response; restoration; tissue regeneration; tissue repair

DESCRIPTION (provided by applicant): This application seeks to study a subpopulation of activated macrophages that we've identified with potent immunoregulatory activity. We will determine if we can exploit these regulatory macrophages (R-Mf) to develop a novel class of anti-inflammatory therapeutics. In Aim 1, we will characterize regulatory macrophages, and identify a panel of R-Mf-specific biomarkers to develop a "signature" for these cells. These biomarkers will be used to determine the various "reprogramming" signals that can give rise to regulatory macrophages and they will enable the identification of these cells in tissue during disease. We propose that the depletion or induction of R-Mf represent new approaches to treat diseases. In Aim 2, we will examine the conversion of classically activated macrophages (Ca- Mf) to regulatory macrophages. We propose that Ca-Mf can control their own activation state by secreting ATP and rapidly converting it to adenosine. Adenosine induces a regulatory macrophage phenotype. In the absence of this conversion, macrophage activation progresses uncontrolled, leading to inflammatory pathology. This represents a new paradigm in (controlling) macrophage activation. We will determine the role that macrophage ectoenzymes, CD39 and CD73, play in promoting the conversion of ATP to adenosine by engineering macrophages to overexpress or lack these ectoenzymes. The biomarkers developed in Aim 1 will help us to identify the induction of regulatory macrophages following their exposure to adenosine. In Aim 3, we will manipulate macrophages to improve human health. We will induce the formation of R-Mf and determine whether the reversal of disease pathology correlates with the induction of regulatory macrophages. We will utilize the "biomarkers" developed in Aim 1 to identify the persistence of R-Mf in tissue during the process of disease resolution. We will generate R-Mf by either adding exogenous 'reprogramming' signals (Aim 1) or by promoting the conversion of ATP to adenosine (Aim 2). The core hypothesis to be tested in these studies is that macrophage physiology can be reliably and predictably manipulated, and that R-Mf can be exploited to modify immune responses and affect disease outcomes. By inducing regulatory macrophages we can prevent or reverse autoimmune pathologies. By deleting regulatory macrophages we may enhance immunity.

描述（由申请人提供）：本申请旨在研究我们已鉴定出具有有效免疫调节活性的活化巨噬细胞亚群。我们将确定是否可以利用这些调节性巨噬细胞（R-Mf）来开发一类新型抗炎疗法。在目标 1 中，我们将表征调节性巨噬细胞，并鉴定一组 R-Mf 特异性生物标志物，以开发这些细胞的“特征”。这些生物标志物将用于确定可产生调节性巨噬细胞的各种“重编程”信号，并且它们将能够在疾病期间识别组织中的这些细胞。我们认为 R-Mf 的消耗或诱导代表了治疗疾病的新方法。在目标 2 中，我们将研究经典激活巨噬细胞 (Ca-Mf) 向调节性巨噬细胞的转化。我们认为 Ca-Mf 可以通过分泌 ATP 并将其快速转化为腺苷来控制自身的激活状态。腺苷诱导调节性巨噬细胞表型。如果没有这种转化，巨噬细胞活化就会不受控制地进行，导致炎症病理学。这代表了（控制）巨噬细胞激活的新范例。我们将通过改造巨噬细胞使其过度表达或缺乏这些胞外酶，确定巨噬细胞胞外酶 CD39 和 CD73 在促进 ATP 转化为腺苷中所起的作用。目标 1 中开发的生物标志物将帮助我们识别调节性巨噬细胞在暴露于腺苷后的诱导。在目标 3 中，我们将操纵巨噬细胞来改善人类健康。我们将诱导 R-Mf 的形成，并确定疾病病理学的逆转是否与调节性巨噬细胞的诱导相关。我们将利用目标 1 中开发的“生物标志物”来识别疾病消退过程中 R-Mf 在组织中的持续存在。我们将通过添加外源“重编程”信号（目标 1）或促进 ATP 转化为腺苷（目标 2）来生成 R-Mf。这些研究要测试的核心假设是巨噬细胞生理学可以可靠且可预测地操纵，并且 R-Mf 可用于改变免疫反应并影响疾病结果。通过诱导调节性巨噬细胞，我们可以预防或逆转自身免疫病理。通过删除调节性巨噬细胞，我们可以增强免疫力。