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: 8082649
• 负责人: Gwendalyn J Randolph
• 金额: $ 28.52万
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8082649
• 关键词: Affect; Agonist; Area; Arterial Fatty Streak; Arteries; Atherosclerosis; Blood; Cells; Data; Dendritic Cells; Development; Diabetes Mellitus; FABP4 gene; Frequencies; Gene Expression; Genes; Home environment; Homeostasis; Homing; 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; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Relative (related person); Research Personnel; Role; Site; Skin; Testing; Therapeutic; 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希望的治疗方法。PPAR的主要目标？作用是单核细胞来源的细胞。在这里，我们的目标是确定TZDs如何影响血液单核细胞及其下游产物-巨噬细胞和树突状细胞（dc）。有两种单核细胞亚群：CCR2+ [Gr-1hi]“炎性”单核细胞很容易被招募到斑块上，而CCR2- [Gr-1hi]血液单核细胞则不太容易被招募到炎症上，包括动脉粥样硬化斑块。这些单核细胞亚群在小鼠和人类之间非常相似。通过基因阵列分析Gr- 1hiCCR2+与Gr- 1loccr2 -造血单核细胞的基因表达模式，发现FABP4/aP2、PPAR？等参与脂质代谢调控和动脉粥样硬化调控的基因在Gr-1loCCR2-血单核细胞中高表达，与“经典”的Gr-1hiCCR2+单核细胞不同。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，tzd可能降低循环CCR2+单核细胞募集到斑块的“可用性”。基因表达谱表明，Gr-1lo单核细胞具有更多的dc样特征，它们可能是TZDs在体内作用的主要靶点。因此，我们将测试PPAR的作用。在维持Gr-1loCCR2-单核细胞池和确定TZD如何改变该池的过程中，影响其激活的基因和内源性途径。我们还将追踪这两个单核细胞亚群的迁移命运，以确定tzd如何影响它们向斑块的募集、斑块内的分化模式，以及可能以dc样细胞的形式向斑块外迁移的潜力。最后，我们的初步数据表明，至少在皮肤等组织中，dc可以被TZDs动员并迁移到淋巴结。tzd引起的DC迁移特别显著，因为tzd似乎不像目前已知的所有其他已定义的DC迁移刺激剂那样诱导迁移DC的成熟。成熟的树突状细胞被认为可以诱导免疫启动，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激活启动的途径。这可能会刺激未成熟的树突状细胞迁移并可能诱导耐受性。我们将研究这种可能性及其与病变前动脉壁dc的相关性。