Cholesterol regulation of Macrophage Inflammation and Vascular Diseases

巨噬细胞炎症和血管疾病的胆固醇调节

• 批准号: 9206076
• 负责人: SHOBHA GHOSH
• 金额: --
• 依托单位: VA VETERANS ADMINISTRATION HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9206076
• 关键词: ATP binding cassette transporter 1; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Atherosclerosis; Attenuated; Bacterial Toxins; CASP1 gene; Cardiovascular Diseases; Cell Surface Proteins; Cell Surface Receptors; Cell physiology; Cell surface; Cellular Membrane; Characteristics; Chemicals; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Chronic; Coronary Arteriosclerosis; Development; Disease; Enzymes; Foam Cells; Future; Generations; Genetic Transcription; Homeostasis; Hydrophobicity; Immune; Infection; Inflammasome; Inflammation; Inflammatory; Injury; Interferon Type I; Interleukin-1; Interleukin-10; Ion Channel; Link; Lipids; Macrophage Activation; Mediating; Membrane Lipids; Membrane Microdomains; Metabolic; Metabolic Diseases; Molecular; Nature; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Pathway interactions; Pattern; Periodicity; Plasma; Population; Potassium Channel; Prevalence; Prevention; Production; Regulation; Role; Sentinel; Signal Transduction; Signaling Protein; Sterility; Syndrome; TLR4 gene; Testing; Transgenic Mice; Transgenic Organisms; Vascular Diseases; Veterans; attenuation; base; burden of illness; clinically relevant; cytokine; design; esterase; extracellular; in vivo; lipid metabolism; macrophage; novel; overexpression; pathogen; public health relevance; restoration; sterol esterase; targeted treatment; therapeutic target; western diet

 DESCRIPTION (provided by applicant): Low grade chronic inflammation associated with obesity is the underlying cause of the development of metabolic diseases including Type 2 diabetes (T2DM) and atherosclerosis. The most important characteristics of chronic inflammation are its persistence and inability to resolve resulting in lack of restoration of homeostasis and development of metabolic diseases. In contrast to classical inflammation which is triggered by an injury or infection, this low grade chronic inflammation is "sterile" in nature without a direct involvement of a pathogen and is often triggered by nutrients and metabolic surplus and hence also referred to as metaflammation meaning metabolically triggered inflammation. Metaflammation is characterized by abnormal cytokine production especially Interleukin-1 (IL-1) and persistent activation of a network of inflammatory pathways. Chronic activation of innate immune sentinels or macrophages underlies this abnormal cytokine production however the cellular mechanisms involved are not completely defined. The production and secretion of IL-1 from macrophages is under very tight regulation which requires coordination of two Signals, namely Signal 1: cellular priming required for inducing transcription (via NF-B), and Signal 2: activation of NLRP3 inflammasome for proteolytic cleavage of pro-IL-1 by active Caspase-1 and secretion of mature IL-1. Increase in cellular lipid accumulation is one of the prominent features of obesity and intracellular lipid metabolism, especially cholesterol metabolism, is tightly linked to the inflammatory status of macrophages. For example, inability to efficiently efflux excess cholesterol due to deficiency of ABCA1 transporter increases cytokine production from macrophages and increase inflammation. Consistently, we have demonstrated that reduction in macrophage cholesterol content by macrophage-specific transgenic over-expression of cholesterylester (CE) hydrolase (CEH, an enzyme that hydrolyzes intracellular stored CE and rate-limits cholesterol efflux) leads to a dramatic (>20 fold) reduction in plasma IL-1 levels. However, the mechanisms underlying the "crosstalk" between cellular cholesterol homeostasis and inflammatory pathways have not been established as yet. Both signals required for activation of inflammatory pathways depend on cell surface proteins: signaling via cell surface receptors (e.g., TLR4) associated with membrane lipid rafts or cholesterol- enriched membrane micro-domains is required for Signal 1 and Signal 2 or NLRP3 activation is triggered by K+ efflux regulated by cell surface-associated ion channels. Since the presence/function of these cell surface receptors and channels depends on the cellular/membrane cholesterol or lipid-raft levels, We hypothesize that CEH-mediated reduction in cellular cholesterol content attenuates 1) the "priming" of macrophages by modulating TLR4 signaling and 2) the "activation" of the inflammasome via changes in cellular K+ efflux and thereby beneficially modulates macrophage function. We propose the following Aims to test the hypothesis: Aim 1: To delineate the mechanisms by which CEH-mediated changes in cellular cholesterol content can modulate macrophage "priming" or Signal 1. Aim 2: To delineate the mechanisms underlying CEH-mediated modulation of "inflammasome activation" or Signal 2 via cellular cholesterol depletion. Aim 3: To evaluate the role of CEH-mediated attenuation of Signal 1 and Signal 2-dependent macrophage activation in modulating inflammation in vivo. These studies will establish that targeted reduction in macrophage cholesterol content would simultaneously attenuate multiple metabolic diseases including Type 2 Diabetes and Coronary Artery Disease (CAD). In addition, the comprehensive approach used will define the pathways by which hydrophobic cholesterol "communicates" with the inflammatory machinery and identify molecular mechanisms that can be explored as potential therapeutic targets in future (e.g., regulating K+ efflux) to modulate other sterile inflammation based diseases.

 描述（由申请人提供）： 与肥胖相关的低年级慢性炎症是代谢性疾病（包括2型糖尿病（T2DM）和动脉粥样硬化）发展的根本原因。慢性炎症的最重要特征是其持久性和无法解决 导致缺乏恢复体内稳态和代谢疾病的发展。与受伤或感染触发的经典感染相反，这种低级慢性感染本质上是“无菌”的，而没有病原体直接参与，并且通常是 由养分和代谢盈余触发，因此也称为元炎症，意味着代谢触发的注射。元炎症的特征是细胞因子异常产生，特别是白介素-1（IL-1）和持续激活的网络 炎症途径。先天免疫哨兵或巨噬细胞的长期激活是这种异常的细胞因子产生的基础，但是涉及的细胞机制尚未完全定义。 巨噬细胞中IL-1的产生和分泌受到非常严格的调节，需要对两个信号进行协调，即信号1：诱导转录所需的细胞启动（通过NF-B）和信号2：NLRP3炎症体的激活，用于通过主动caspase-1和分配的pro-1蛋白水解裂解的蛋白水解裂解和分配的蛋白质裂解。细胞脂质积累的增加是肥胖和细胞内脂质代谢的重要特征之一，尤其是胆固醇代谢，与巨噬细胞的炎症状态紧密相关。例如，由于ABCA1转运蛋白的变形，无法有效地排出超过胆固醇会增加巨噬细胞的细胞因子产生并增加炎症。一致地，我们已经证明，通过巨噬细胞特异性转基因过表达胆固醇（CE）水解酶（CEH）（CEH，一种水解细胞内储存的CE和速率限制胆固醇外排）的酶降低了巨噬细胞胆固醇含量。但是，尚未确定细胞胆固醇稳态和炎症途径之间“串扰”的机制。激活炎症途径所需的两个信号都取决于细胞表面蛋白：通过细胞表面受体（例如，TL​​R4）信号传导与膜脂质筏或胆固醇富含膜的膜微域相关的信号1和信号2或NLRP3激活受到k+ Efflux调节的信号2或NLRP3激活所必需的。由于这些细胞表面受体和通道的存在/功能取决于细胞/膜胆固醇或脂质抗体水平，我们假设CEH介导的细胞胆固醇含量减少了1）巨噬细胞的“启动”巨噬细胞的“启动”，通过调节TLR4信号的调节和2）通过将其激活的kirffffect andy forgefffirction forkiandy变化而变化。巨噬细胞功能。我们提出以下旨在检验假设的目的：目标1：描绘CEH介导的细胞胆固醇含量变化的机制可以调节巨噬细胞“启动”或信号1。目标2：划定CEH介导的CEH介导的“炎性型” ORSICEL 2通过CELMASOMES AIRSICLATION AIRMASITARITAL OELSTERATION CALMASITAL AIMBAILATION ACTURATARITAL OELSTERATION OELSTERATION OELSTERATION OELSTERATION cLAMESTORAME AIMERTARITAL OELSTORATION cLAMESTORAME链球菌DEPLENION的机制。目标3：评估CEH介导的信号1的衰减和信号2依赖性巨噬细胞激活在体内调节炎症中的作用。这些研究将确定，巨噬细胞胆固醇含量的靶向降低将简单地减少多种代谢疾病，包括2型糖尿病和冠状动脉疾病（CAD）。此外，所使用的综合方法将定义疏水胆固醇与炎症机制的“通信”的途径，并确定可以作为未来的潜在治疗靶标（例如，调节K+ EFFLUX）调节其他基于无菌的疾病的分子机制。