Pathways that regulate monocyte/dendritic cell migration

调节单核细胞/树突状细胞迁移的途径

• 批准号: 7319784
• 负责人: Gwendalyn J Randolph
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7319784
• 关键词: Affect; Agonist; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood; Cells; Class; Data; Dendritic Cells; Development; Diabetes Mellitus; Disease regression; Frequencies; Gene Expression; Genes; Home environment; Homeostasis; Human; IL2RA gene; Immune; Immune System Diseases; Immune Tolerance; Inflammation; Inflammatory; Lead; Ligands; Lipids; Mediator of activation protein; Methods; Modeling; Molecular Profiling; Mus; Nuclear Receptors; PPAR gamma; Pathway interactions; Pattern; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Phenotype; RNA Interference; Rate; Recruitment Activity; Regulation; Relative (related person); Research Personnel; Role; Site; Skin; Testing; Therapeutic; Thinking; Tissues; adipocyte differentiation; cell motility; cellular targeting; follow-up; glucose metabolism; heart allograft; in vivo; lipid metabolism; lymph nodes; macrophage; macrophage product; migration; monocyte; response; scavenger receptor

DESCRIPTION (provided by applicant): PPAR? agonists like TZDs are promising therapeutics to treat diabetes and atherosclerosis. Major targets of PPAR? action are monocyte-derived cells. Here, we aim to define how TZDs impact blood monocytes and their downstream products-macrophages and dendritic cells (DCs)-in vivo. There are two monocyte subsets: CCR2+ [Gr-1hi] "inflammatory" monocytes that are readily recruited to plaques and CCR2- [Gr-1lo] blood monocytes that are less robustly recruited to inflammation, including atherosclerotic plaques. These monocyte subsets are remarkably similar between mouse and humans. Gene expression patterns of Gr- 1hiCCR2+ versus Gr-1loCCR2- blood monocytes, analyzed herein by gene array, reveal that FABP4/aP2, PPAR?, and other genes involved in regulation of lipid metabolism and regulation of atherosclerosis are highly expressed in Gr-1loCCR2- blood monocytes, in contrast to "classical" Gr-1hiCCR2+ monocytes. Our preliminary data lead us to hypothesize that TZDs can prompt Gr-1hiCCR2+ monocytes to convert to Gr- 1loCCR2- monocytes; by prompting subset conversion, TZDs may reduce 'availability' of circulating CCR2+ monocytes for recruitment into plaques. The gene expression profiles suggest that Gr-1lo monocytes possess a more DC-like character and that they may be primary targets for the action of TZDs in vivo. Thus, we will test the role of the PPAR? gene and endogenous pathways that would affect its activation in maintaining the pool of Gr-1loCCR2- monocytes and determine how TZD alter this pool. We will also trace the migratory fate of both monocyte subsets to define how TZDs affect their recruitment to plaques, differentiation patterns within plaques, and potential to emigrate out of plaques, likely in the form of DC-like cells. Finally, our preliminary data indicate that DCs, at least in tissues like skin, can be mobilized to emigrate to lymph nodes by TZDs. TZD-prompted DC mobilization is particularly remarkable because the TZDs do not appear to induce maturation of the migrating DCs, as all other defined DC migration stimulants known so far. Mature DCs are thought to induce immune priming, but immature DCs are thought to be able to induce immune tolerance. Thus, our studies may be the first to uncover a pathway-initiated by activation of PPAR? in DCs-that could stimulate immature DCs to migrate and possibly induce tolerance. We will study this possibility and its relevance to artery wall DCs that accumulate in prelesional areas.

描述(由申请人提供)：PPAR？像TZDS这样的激动剂是治疗糖尿病和动脉粥样硬化的有前途的治疗药物。PPAR的主要目标是？作用的是单核细胞来源的细胞。在这里，我们的目标是定义TZDS如何在体内影响单核细胞及其下游产物-巨噬细胞和树突状细胞(DC)。有两个单核细胞亚群：CCR2+[Gr-1hi]“炎性”单核细胞很容易被招募到斑块中，以及CCR2-[Gr-1lo]血液中的单核细胞不那么强烈地被招募到炎症中，包括动脉粥样硬化斑块。这些单核细胞亚群在老鼠和人类之间非常相似。通过基因芯片分析Gr-1hiCCR2+与Gr-1loCCR2-单核细胞的基因表达模式，发现FABP4/aP2、PPAR？等参与调节脂代谢和动脉粥样硬化调节的基因在Gr-1loCCR2-单核细胞中高表达，而经典的Gr-1hiCCR2+单核细胞则高表达。我们的初步数据使我们假设TZDS可以促使Gr-1hiCCR2+单核细胞转化为Gr-1loCCR2-单核细胞；通过促进亚群转换，TZDS可能会减少循环中CCR2+单核细胞重新聚集到斑块中的可能性。基因表达谱表明，Gr-1lo单核细胞具有更类似DC的特性，可能是TZDS体内作用的主要靶点。因此，我们将测试PPAR的作用？基因和内源性途径将影响其在维持Gr-1loCCR2-单核细胞池中的激活，并决定TZD如何改变这一池。我们还将追踪这两个单核细胞亚群的迁移命运，以确定TZD如何影响它们在斑块中的募集、斑块内的分化模式以及可能以DC样细胞的形式从斑块中迁移出来。最后，我们的初步数据表明，至少在皮肤等组织中，TZDS可以动员DC迁移到淋巴结。TZD促进的DC动员尤其值得注意，因为TZD似乎并不像迄今已知的所有其他已定义的DC迁移刺激剂那样诱导迁移的DC成熟。成熟的树突状细胞被认为能够诱导免疫启动，但不成熟的树突状细胞被认为能够诱导免疫耐受。因此，我们的研究可能是第一个发现由PPAR激活启动的通路。在DC中，这可能会刺激未成熟的DC迁移，并可能诱导耐受性。我们将研究这种可能性及其与皮损前区域聚集的动脉壁树突状细胞的相关性。