Role of Macrophage Arginase in Anti-Bacterial Immunity

巨噬细胞精氨酸酶在抗细菌免疫中的作用

• 批准号: 7531056
• 负责人: PETER J. MURRAY
• 金额: $ 24.42万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531056
• 关键词: Acute; Address; Affect; Agonist; Anabolism; Anti-Bacterial Agents; Arginine; Asthma; Bacteria; Bacterial Infections; Binding; Biochemical; Biogenesis; Bioinformatics; Biology; Cell Culture Techniques; Cessation of life; Chronic; Chronic Disease; Collagen; Communicable Diseases; Data; Disease; Elements; Enhancers; Failure; Fibrosis; Generations; Granuloma; Hand; Helminths; Hydrolysis; Immune; Immune response; Immunity; In Vitro; Infection; Infectious Agent; Inflammation; Inflammatory; Interleukin-13; Interleukin-4; Kinetics; Knock-out; Link; Mediating; Modeling; Molecular; Mouse Strains; Mus; Mycobacterium Infections; Nitric Oxide; Nitric Oxide Synthase; Ornithine; Outcome; Oxygen; Pathway interactions; Play; Production; Proline; Proteins; Recovery; Regulation; Regulatory Element; Research; Role; Sepsis; Septic Shock; Signal Transduction; Staging; Stimulus; System; Techniques; Tissues; Toll-like receptors; Transgenic Mice; Translating; Translations; Tuberculosis; Urea; Wound Healing; arginase; chromatin immunoprecipitation; in vivo; in vivo Model; insight; liver function; macrophage; microbicide; mouse model; mycobacterial; overexpression; pathogen; promoter; response; tool

DESCRIPTION (PROVIDED BY APPLICANT): The tight control of macrophage function is central to inflammatory and immune responses. Arginase I (Arg I) is a newly recognized marker of activated macrophages. The profound induction of normally silent Arg I expression in response to infectious agents, in asthma and in other diseases involving chronic inflammation suggests that new insights into macrophage function in immunity can be uncovered by understanding the biology of Arg I, and the pathways that converge to regulate its expression. However, a major gap in understanding Arg I function in the context of immune responses is the translation of correlative expression data and in vitro findings to in vivo systems because Arg I also plays an irreplaceable role in liver function. To address this problem, mouse models were developed where Arg I is specifically deleted or over-expressed in macrophages. The preliminary data establish the fidelity of these models and set the stage for a detailed examination of Arg I function in immune responses to bacteria. Infection models will be studied because Arg I function is most directly implicated in two pathways that regulate immunity to bacteria: nitric oxide (NO) biosynthesis and the promotion of fibrosis. Four aims are proposed to study Arg I biology in macrophages. In Aim 1, the role of Arg I in regulating the biogenesis of NO will be studied using systems deficient in Arg I. In Aim 2, the role of Arg I in regulating inflammation, tissue repair and NO biosynthesis in septic shock models will be dissected. In Aim 3, the function of Arg I in regulating the immunological and pathological outcomes in tuberculosis, a chronic disease that is dependent on exquisite control of NO levels for effective immunity, will be investigated. In Aim 4, we will extend our current studies of Arg I regulation in macrophages to determine how pathogens themselves induce expression. The outcomes of the proposed studies will reveal new elements of Arg I function and provide rationale for approaching Arg I as a target in inflammatory diseases.

描述(申请人提供)：巨噬细胞功能的严格控制是炎症和免疫反应的中心。精氨酸酶I(Arg I)是新近发现的激活巨噬细胞的标志物。在感染因子、哮喘和其他涉及慢性炎症的疾病中，正常沉默的Arg I表达的深刻诱导表明，通过了解Arg I的生物学以及聚集到一起调节其表达的途径，可以发现对巨噬细胞在免疫中的功能的新见解。然而，在免疫应答的背景下理解Arg I功能的一个主要差距是将相关的表达数据和体外研究结果转换到体内系统，因为Arg I在肝功能中也发挥着不可替代的作用。为了解决这个问题，建立了小鼠模型，其中Arg I在巨噬细胞中特异性地缺失或过度表达。初步数据建立了这些模型的保真度，并为详细研究Arg I在细菌免疫反应中的作用奠定了基础。感染模型将被研究，因为Arg I功能最直接地涉及调节细菌免疫的两条途径：一氧化氮(NO)的生物合成和促进纤维化。提出了研究巨噬细胞Arg I生物学的四个目标。在目标1中，将利用Arg I缺乏的系统来研究Arg I在调控NO生物发生中的作用。在目标2中，将剖析Arg I在感染性休克模型中调节炎症、组织修复和NO生物合成的作用。在目标3中，将研究Arg I在调节结核病的免疫和病理结果中的作用。结核病是一种慢性疾病，依赖于对NO水平的精确控制来获得有效的免疫。在目标4中，我们将扩展我们目前对巨噬细胞中Arg I调控的研究，以确定病原体本身是如何诱导表达的。拟议的研究结果将揭示Arg I功能的新元素，并为将Arg I作为炎症性疾病的靶点提供理论依据。

项目成果

Arginine usage in mycobacteria-infected macrophages depends on autocrine-paracrine cytokine signaling.

• DOI: 10.1126/scisignal.2000955
• 发表时间: 2010-08-17
• 期刊: Science signaling
• 影响因子: 7.3
• 作者: Qualls JE;Neale G;Smith AM;Koo MS;DeFreitas AA;Zhang H;Kaplan G;Watowich SS;Murray PJ
• 通讯作者: Murray PJ

Stress Kinase GCN2 Controls the Proliferative Fitness and Trafficking of Cytotoxic T Cells Independent of Environmental Amino Acid Sensing.

• DOI: 10.1016/j.celrep.2016.10.079
• 发表时间: 2016-11-22
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Van de Velde LA;Guo XJ;Barbaric L;Smith AM;Oguin TH 3rd;Thomas PG;Murray PJ
• 通讯作者: Murray PJ

Arginase-1-expressing macrophages are dispensable for resistance to infection with the gastrointestinal helminth Trichuris muris.

• DOI: 10.1111/j.1365-3024.2011.01300.x
• 发表时间: 2011-07
• 期刊: Parasite immunology
• 影响因子: 2.2
• 作者: Bowcutt R;Bell LV;Little M;Wilson J;Booth C;Murray PJ;Else KJ;Cruickshank SM
• 通讯作者: Cruickshank SM

Arginase-1-expressing macrophages suppress Th2 cytokine-driven inflammation and fibrosis.

• DOI: 10.1371/journal.ppat.1000371
• 发表时间: 2009-04
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Pesce JT;Ramalingam TR;Mentink-Kane MM;Wilson MS;El Kasmi KC;Smith AM;Thompson RW;Cheever AW;Murray PJ;Wynn TA
• 通讯作者: Wynn TA

Autocrine IL-10 induces hallmarks of alternative activation in macrophages and suppresses antituberculosis effector mechanisms without compromising T cell immunity.

• DOI: 10.4049/jimmunol.0803567
• 发表时间: 2009-07-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Schreiber T;Ehlers S;Heitmann L;Rausch A;Mages J;Murray PJ;Lang R;Hölscher C
• 通讯作者: Hölscher C