Mechanisms of Chronic Nod2-mediated Effects in Human Macrophages

Nod2 介导的人巨噬细胞慢性作用的机制

• 批准号: 7656767
• 负责人: CLARA ABRAHAM
• 金额: $ 33.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-11 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7656767
• 关键词: Abbreviations; Acetylmuramyl-Alanyl-Isoglutamine; Acute; Address; Affect; Antigen-Presenting Cells; Arrestins; Bacteria; Boxing; Caspase; Cell Nucleus; Cell Wall; Cells; Chronic; Crohn' s disease; Cytoplasm; Defect; Dendritic Cells; Development; Down-Regulation; Environment; Equilibrium; Exhibits; Exposure to; Figs - dietary; Functional disorder; Genetic Polymorphism; Hand; Heterogeneity; Human; Hydrochloride Salt; IRAK1 gene; IRAK3 gene; Immune system; Individual; Individual Differences; Inflammatory; Inflammatory Bowel Diseases; Intestines; Lead; Leucine-Rich Repeat; Ligands; MAP Kinase Gene; MAP3K7 gene; MAPK14 gene; MAPK8 gene; Mediating; Mitogen-Activated Protein Kinases; Mutation; Nucleotides; Organism; Outcome; Pathway interactions; Pattern recognition receptor; Peptidoglycan; Peripheral; Production; Proteins; RIPK2 gene; Role; Signal Pathway; Signal Transduction; TLR2 gene; TLR4 gene; TNFRSF5 gene; TOLLIP gene; TRAF6 gene; Testing; Tissues; Toll-Like Receptor 2; Toll-Like Receptor Pathway; Toll-like receptors; Transcriptional Activation; Ulcerative Colitis; Up-Regulation; base; comparative; cytokine; gastrointestinal; human IRAK1 protein; human disease; innovation; insight; loss of function; macrophage; microbial; monocyte; peptidoglycan receptor; public health relevance; receptor; response

DESCRIPTION (provided by applicant): A unique challenge faced by the intestinal immune system is the requirement for tolerance to luminal bacteria while simultaneously defending against pathogenic organisms. The dysregulation of this balance can lead to uncontrolled activation of the gastrointestinal immune system, a feature of Crohn's disease and ulcerative colitis. The recognition and response to microbial organisms is mediated in part by pattern recognition receptors (PRR), which include nucleotide oligomerization domain 2 (NOD2), an intracellular bacterial recognition receptor for peptidoglycan (PGN), a component of both gram positive and gram negative cell walls. Crohn's disease is associated with loss-of-function polymorphisms in NOD2 (CARD15). However, the specific NOD2 dysfunction(s) leading to the development of Crohn's disease is not yet understood. Upon acute stimulation of NOD2, either alone or in combination with other bacterial receptors, peripherally-derived antigen presenting cells (APC) secrete proinflammatory cytokines. Intestinal macrophages and dendritic cells (DC) are in large part derived from circulating monocytes that migrate into the intestinal tissues and undergo differentiation based on the intestinal environment. The intestinal immune system is an environment which results in chronic stimulation. Therefore, it is critical to understand the consequences of chronic stimulation through NOD2. We have recently found that chronic stimulation through NOD2 in primary peripheral monocyte-derived human macrophages results in reduced production of pro- inflammatory cytokines upon restimulation either through NOD2 or through other PRR. This downregulation in production of pro-inflammatory cytokine secretion is similar to the tolerance, or significantly reduced secretion of pro-inflammatory cytokines, exhibited by intestinal macrophages stimulated with bacterial products. On the other hand, intestinal APC from individuals with inflammatory bowel disease (IBD) have excess production of pro-inflammatory cytokines. We hypothesize that the tolerance induced in primary human APC upon stimulation through NOD2 is mediated by a combination of mechanisms that selectively affect specific signaling pathways (e.g. pro-inflammatory cytokines), and that some of these mechanisms are different than those mediated by chronic stimulation of Toll like receptors (TLR). This proprosal will define the tolerance defects in human peripheral macrophages expressing the various Crohn's disease- associated NOD2 mutations, the mechanisms mediating peripheral macrophage tolerance through chronic NOD2 versus TLR stimulation, and then extend these findings directly into human intestinal macrophages. PUBLIC HEALTH RELEVANCE We have recently found that chronic stimulation through NOD2 in primary peripheral monocyte-derived human macrophages results in reduced production of proinflammatory cytokines upon restimulation either through NOD2 or through other pattern recognition receptors. We seek to define the combination of NOD2-mediated mechanisms that selectively affect the downregulation of these pro-inflammatory cytokines, and determine if these mechanisms are different from those induced upon chronic stimulation of Toll like receptors. We will then extend these findings directly into human intestinal macrophages and determine if individuals harboring Crohn's disease associated NOD2 mutations are defective in these mechanisms.

描述（由申请人提供）：肠道免疫系统面临的独特挑战是对腔细菌的耐受性的要求，同时捍卫了针对致病生物。这种平衡的失调可能导致胃肠道免疫系统的激活不受控制，这是克罗恩病和溃疡性结肠炎的特征。对微生物生物的识别和反应部分是由模式识别受体（PRR）介导的，该受体包括核苷酸寡聚结构域2（NOD2），这是肽聚糖（PGN）的细胞内细菌识别受体，这是革兰氏阳性和革兰氏阴性细胞的一个成分。克罗恩病与NOD2的功能丧失多态性有关（CARD15）。但是，尚不清楚导致克罗恩病发展的特定NOD2功能障碍。急性刺激NOD2，无论是单独还是与其他细菌受体结合，周围衍生的抗原呈现细胞（APC）分泌促炎细胞因子。肠道巨噬细胞和树突状细胞（DC）在很大程度上源自循环的单核细胞，这些单核细胞迁移到肠道组织中，并根据肠道环境进行分化。肠道免疫系统是导致慢性刺激的环境。因此，了解通过NOD2的慢性刺激的后果至关重要。我们最近发现，在原代外周单核细胞衍生的人类巨噬细胞中通过NOD2进行慢性刺激导致促炎性细胞因子通过NOD2或通过其他PRR的产生降低。促炎性细胞因子分泌产生的下调类似于耐受性，或显着降低了被细菌产物刺激的肠道巨噬细胞所表现出的促炎细胞因子的分泌。另一方面，来自炎症性肠病患者（IBD）的肠道APC过量产生促炎性细胞因子。我们假设通过NOD2刺激后，在原代人APC中诱导的耐受性是由选择性影响特定信号通路（例如促炎细胞因子）的机制组合介导的，并且其中一些机制与通过慢性刺激受体（TLR）介导的机制不同。该预言将定义表达各种克罗恩病与疾病相关的NOD2突变的人类外周巨噬细胞中的耐受性缺陷，通过慢性NOD2与TLR刺激介导的机制介导了外周巨噬细胞耐受性，然后将这些发现直接扩展到人类的肠道巨噬细胞中。 我们最近发现，在原发性单核细胞衍生的人类巨噬细胞中，通过NOD2慢性刺激导致促炎细胞因子通过NOD2或通过其他模式识别受体的产生减少。我们试图定义NOD2介导的机制的组合，这些机制有选择地影响这些促炎性细胞因子的下调，并确定这些机制是否与慢性刺激Toll类似受体诱导的机制是否不同。然后，我们将把这些发现直接扩展到人类肠道巨噬细胞中，并确定与克罗恩病有关的个体与与NOD2相关的nod2突变是否有缺陷。