Efferocytosis in Lyme Arthritis Resolution

莱姆关节炎解决中的胞吞作用

• 批准号: 9894168
• 负责人: Charles R. Brown
• 金额: $ 18.71万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-14 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9894168
• 关键词: Acute; Anti-Inflammatory Agents; Antibodies; Apoptosis; Apoptotic; Arachidonate 15-Lipoxygenase; Arachidonic Acids; Arthritis; Asthma; Autoimmune Process; Automobile Driving; B-Lymphocytes; Bacteria; Blood Circulation; Borrelia burgdorferi; CD36 gene; Cardiovascular Diseases; Cell Culture Techniques; Cells; Chronic; Cytochrome P450; Data; Development; Disease; Down-Regulation; Eicosanoids; Excision; Experimental Models; Exposure to; Extravasation; Failure; Homeostasis; Host Defense; Inbred C3H Mice; Infection; Infectious Agent; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Arthritis; Inflammatory Response; Interleukin-10; Joints; LOX gene; Lead; Lipids; Lipoxygenase; Lyme Arthritis; Malignant Neoplasms; Mediating; Mediator of activation protein; Membrane; Metabolic Pathway; Microbe; Modernization; Mus; Natural Immunity; Necrosis; Neutrophil Infiltration; Nuclear; Omega-3 Fatty Acids; Order Spirochaetales; PTGS2 gene; Pathway interactions; Phenotype; Play; Process; Production; Prostaglandin-Endoperoxide Synthase; Reporting; Resolution; Risk; Role; Secondary to; Severities; Signal Transduction; Site; Syndrome; System; Systemic Lupus Erythematosus; T-Lymphocyte; Therapeutic; Therapeutic Effect; Time; Tissues; Up-Regulation; Work; chemokine; chronic inflammatory disease; cytokine; eicosanoid metabolism; experimental study; fatty acid metabolism; healing; in vivo; interest; lipid mediator; macrophage; microbial; monocyte; mouse model; neutrophil; new therapeutic target; pathogenic microbe; prevent; response; response to injury; restoration; scavenger receptor; therapy design; uptake

Abstract Inflammation is a beneficial response to infection or tissue damage and mediates the removal of microbial pathogens and restoration of the tissue to homeostasis. Occasionally the inflammatory response does not resolve properly and becomes chronic. Chronic inflammation is considered the underlying cause of many diseases of the modern world, such as arthritis, asthma, and many others, and much effort has gone into trying to block the development of inflammation. However, these approaches also increase the risk of serious infection due to simultaneous inhibition of host defense against microbial pathogens. Recent work has demonstrated that resolution of inflammation is an active process. Thus, therapeutics may be developed capable of inducing resolution of chronic inflammatory disease. The clearance of apoptotic cells (AC) from the inflammatory site has been identified as a key component of the resolution process. The uptake of AC by inflammatory macrophages (efferocytosis) induces their down-regulation of pro-inflammatory cytokines and up- regulation of anti-inflammatory mediators, increases efferocytosis, inhibits further neutrophil recruitment, and promotes tissue healing and homeostasis. In addition, the clearance of AC also prevents their undergoing secondary necrosis, leaking cytosolic contents and prolonging inflammation. Thus, a more complete understanding how efferocytosis modulates macrophages from pro-inflammatory to pro-resolution is needed. Eicosanoids are powerful lipid mediators derived from the metabolism of arachidonic acid. They mediate many aspects of the inflammatory response and play important roles in resolution. Omega-3 fatty acid metabolism produces a class of lipids called specific pro-resolving mediators (SPM) capable of inducing resolution of inflammation. My lab is interested in defining the mechanisms used by eicosanoids and SPM to induce the resolution of inflammatory disease. We use a mouse model of Lyme arthritis caused by infection of C3H mice with the spirochete, B. burgdorferi. This proposal has two specific aims: Aim 1 will explore the mechanism of how AC engulfment by inflammatory macrophages alters their function. We will determine the roles of various eicosanoid metabolic pathways (COX, 5-LOX and 12/15-LOX) and SPM in these responses. Aim 2 will explore the enhanced effect of activated AC (previous exposure to bacteria) on arthritis resolution, and the roles of eicosanoids and SPM in this process. Successful completion of these aims will lay the groundwork for further studies to elucidate the regulatory mechanisms of how, during an infectious inflammatory response, the system switches from pro-inflammatory to pro-resolution and the impact infectious agents have on this decision. These studies will broaden our understanding of inflammatory disease and may impact our ability to lessen chronic inflammation while sparing host defense.

摘要 炎症是对感染或组织损伤的有益反应，并介导微生物的清除。 病原体和恢复组织的稳态。有时炎症反应并不 解决得当，成为慢性病。慢性炎症被认为是许多疾病的根本原因。 现代世界的疾病，如关节炎，哮喘，和许多其他人，和许多努力已经进入尝试 阻止炎症的发展然而，这些方法也增加了严重的风险。 由于同时抑制宿主对微生物病原体的防御而引起的感染。最近的工作已经 表明炎症的消退是一个积极的过程。因此，可以开发治疗剂， 能够诱导慢性炎性疾病的消退。凋亡细胞（AC）从 炎症部位已被确定为消退过程的关键组成部分。AC的摄取， 炎性巨噬细胞（巨噬细胞增多症）诱导其促炎细胞因子的下调和促炎细胞因子的上调， 调节抗炎介质，增加红细胞增多，抑制进一步的中性粒细胞募集， 促进组织愈合和体内平衡。此外，AC的清除也阻止了它们的进行 继发性坏死、胞浆内容物渗漏和炎症延长。因此，更完整的 需要了解巨噬细胞增多症如何调节巨噬细胞从促炎到促消退。 类二十烷酸是由花生四烯酸代谢产生的强有力的脂质介质。他们调解了许多 炎症反应的各个方面，并在解决中发挥重要作用。ω-3脂肪酸代谢 产生一类称为特异性促消退介质（SPM）的脂质，能够诱导 炎症我的实验室有兴趣定义类花生酸和SPM诱导 炎症性疾病的消退。我们使用由C3 H小鼠感染引起的莱姆关节炎小鼠模型 和螺旋体的关系B burgdorferi。该提案有两个具体目标：目标1将探讨 炎症性巨噬细胞吞噬AC如何改变其功能。我们将确定各种角色 类二十烷酸代谢途径（考克斯、5-LOX和12/15-LOX）和SPM在这些响应中的作用。Aim 2将探索 活化AC（先前暴露于细菌）对关节炎消退的增强作用，以及 类花生酸和SPM在这个过程中。这些目标的成功实现将为今后的工作奠定基础。 研究阐明了在感染性炎症反应过程中， 从促炎到促消退的转变，以及感染因子对这一决定的影响。这些 研究将拓宽我们对炎症性疾病的理解，并可能影响我们减轻慢性炎症的能力。 炎症，同时避免宿主防御。