Regulatory macrophages and the host inflammatory response

调节性巨噬细胞和宿主炎症反应

• 批准号: 9021661
• 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/9021661
• 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; biomarker panel; immunopathology; improved; macrophage; novel; novel strategies; overexpression; prevent; response; restoration; specific biomarkers; 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具有强效免疫调节活性的活化巨噬细胞亚群。我们将确定我们是否可以利用这些调节性巨噬细胞（R-Mf）来开发一类新的抗炎治疗药物。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以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。我们提出，耗竭或诱导R-Mf代表治疗疾病的新方法。在目标2中，我们将研究经典活化的巨噬细胞（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并迅速将其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。在没有这种转化的情况下，巨噬细胞活化不受控制地进行，导致炎症病理学。这代表了（控制）巨噬细胞活化的新范例。我们将确定的作用，巨噬细胞胞外酶，CD 39和CD 73，通过工程巨噬细胞过度表达或缺乏这些胞外酶，促进ATP转化为腺苷。目标1中开发的生物标志物将帮助我们识别暴露于腺苷后调节性巨噬细胞的诱导。在目标3中，我们将操纵巨噬细胞以改善人类健康。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”来鉴定疾病消退过程中组织中R-Mf的持久性。我们将通过添加外源性“重编程”信号（目标1）或通过促进ATP转化为腺苷（目标2）来产生R-Mf。在这些研究中要测试的核心假设是，巨噬细胞生理学可以可靠和可预测地操纵，并且R-Mf可以被利用来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性病变。通过删除调节性巨噬细胞，我们可以增强免疫力。

项目成果

Monocyte subpopulations as important biomarkers of resistence and susceptibility during experimental infection with Leishmania (Leishmania) major.

• DOI: 10.1016/j.biopha.2018.08.154
• 发表时间: 2018-11
• 期刊: Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
• 作者: Martins TAF;Barbosa VS;Almeida GG;Antonelli LRDV;Tafuri WL;Mosser DM;Gonçalves R
• 通讯作者: Gonçalves R

Pattern recognition receptors in innate immunity, host defense, and immunopathology.

• DOI: 10.1152/advan.00058.2013
• 发表时间: 2013-12
• 期刊: Advances in physiology education
• 影响因子: 2.1
• 作者: Rahul Suresh;D. Mosser

IFN-γ Prevents Adenosine Receptor (A2bR) Upregulation To Sustain the Macrophage Activation Response.

• DOI: 10.4049/jimmunol.1501139
• 发表时间: 2015-10-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Cohen HB;Ward A;Hamidzadeh K;Ravid K;Mosser DM
• 通讯作者: Mosser DM

Immune Complex-Driven Generation of Human Macrophages with Anti-Inflammatory and Growth-Promoting Activity.

• DOI: 10.4049/jimmunol.1901382
• 发表时间: 2020-07-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)

Neutrophils have a protective role during early stages of Leishmania amazonensis infection in BALB/c mice.

• DOI: 10.1111/pim.12078
• 发表时间: 2014-01
• 期刊: Parasite immunology
• 影响因子: 2.2
• 作者: Sousa LM;Carneiro MB;Resende ME;Martins LS;Dos Santos LM;Vaz LG;Mello PS;Mosser DM;Oliveira MA;Vieira LQ
• 通讯作者: Vieira LQ