Efferocytosis in Lyme Arthritis Resolution

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 病原体和组织恢复到动态平衡。有时炎症反应不会 妥善解决，就会变成慢性疾病。慢性炎症被认为是许多 现代世界的疾病，如关节炎、哮喘和许多其他疾病，已经付出了很大的努力 以阻止炎症的发展。然而，这些方法也增加了严重的 由于同时抑制宿主对微生物病原体的防御而导致的感染。最近的工作有 证明了炎症的消退是一个活跃的过程。因此，治疗学可以被开发出来 能够诱导慢性炎症性疾病的消退。凋亡细胞(AC)的清除 炎症部位已被确定为解决过程的关键组成部分。人体对AC的摄取 炎性巨噬细胞(泡沫化)诱导它们下调促炎细胞因子和上调- 调节抗炎介质，增加泡腾作用，抑制中性粒细胞进一步募集，以及 促进组织愈合和动态平衡。此外，AC的清除也阻止了他们的经历 继发性坏死，胞浆内容物渗漏，炎症延长。因此，一个更完整的 需要了解吞噬作用如何将巨噬细胞从促炎状态调节为促消解状态。 二十碳二烯类化合物是花生四烯酸代谢过程中产生的一种强有力的脂质介体。他们调解了许多人 炎症反应的方方面面，并在消退中发挥重要作用。Omega-3脂肪酸代谢 产生一类称为特异性促分解介体(SPM)的脂类，能够诱导 发炎。我的实验室感兴趣的是定义二十烷类化合物和SPM用于诱导 消退炎症性疾病。我们使用了一种由C3H小鼠感染引起的莱姆关节炎的小鼠模型 带有螺旋体的伯氏杆菌。这项提议有两个具体目标：目标1将探索 炎症巨噬细胞吞噬AC是如何改变其功能的。我们将确定不同的角色 二十烷类代谢途径(COX、5-LOX和12/15-LOX)和SPM在这些反应中的作用。《目标2》将探索 活化的AC(先前接触细菌)对关节炎消退的增强作用，以及 二十烷类化合物和SPM在这一过程中。这些目标的成功实现将为进一步 研究阐明在感染性炎症反应期间，系统如何调节机制 从促炎到促消解的转变以及感染剂对这一决定的影响。这些 研究将扩大我们对炎症性疾病的理解，并可能影响我们缓解慢性疾病的能力 炎症，同时避免宿主防御。

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.