Pathways that regulate monocyte/dendritic cell migration

调节单核细胞/树突状细胞迁移的途径

基本信息

项目摘要

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?激动剂如TZD是治疗糖尿病和动脉粥样硬化的有希望的治疗剂。PPAR的主要目标?作用是单核细胞衍生的细胞。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)-在体内。有两种单核细胞亚群:CCR 2 + [Gr-1hi]“炎性”单核细胞,其容易募集到斑块中;以及CCR 2- [Gr-1 lo]血液单核细胞,其不太稳健地募集到炎症,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。本文通过基因阵列分析的Gr-1hiCCR 2+与Gr-1 loCCR 2-血单核细胞的基因表达模式显示,FABP 4/aP 2、PPAR?与“经典的”Gr-1hiCCR 2+单核细胞相反,在Gr-1 loCCR 2-血单核细胞中高度表达参与脂质代谢调节和动脉粥样硬化调节的其他基因。我们的初步数据使我们假设TZDs可以促使Gr-1hiCCR 2+单核细胞转化为Gr-1 loCCR 2-单核细胞;通过促进亚群转化,TZDs可能降低循环CCR 2+单核细胞招募到斑块中的“可用性”。基因表达谱表明,Gr-1 lo单核细胞具有更多的DC样特征,它们可能是TZDs体内作用的主要靶点。因此,我们将测试的作用,过氧化物酶体增殖物激活受体?基因和内源性途径,这将影响其激活,维持池的Gr-1 loCCR 2单核细胞,并确定如何TZD改变这个池。我们还将追踪这两种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样细胞的形式迁移出斑块的潜力。最后,我们的初步数据表明,树突状细胞,至少在组织如皮肤,可以动员迁移到淋巴结的TZDs。TZD促进的DC动员是特别显著的,因为TZD似乎不诱导迁移DC的成熟,如迄今为止已知的所有其他定义的DC迁移刺激剂。成熟的DC被认为诱导免疫启动,但不成熟的DC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的途径启动激活的过氧化物酶体增殖物激活受体?在DC中-其可刺激未成熟DC迁移并可能诱导耐受。我们将研究这种可能性及其与在病变前区域积聚的动脉壁DC的相关性。

项目成果

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Gwendalyn J Randolph其他文献

Proliferating macrophages prevail in atherosclerosis
增殖的巨噬细胞在动脉粥样硬化中占优势
  • DOI:
    10.1038/nm.3316
  • 发表时间:
    2013-09-06
  • 期刊:
  • 影响因子:
    50.000
  • 作者:
    Gwendalyn J Randolph
  • 通讯作者:
    Gwendalyn J Randolph

Gwendalyn J Randolph的其他文献

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{{ truncateString('Gwendalyn J Randolph', 18)}}的其他基金

Mechanisms that alter lymphatic transport in inflammatory bowel disease
改变炎症性肠病淋巴运输的机制
  • 批准号:
    10420703
  • 财政年份:
    2022
  • 资助金额:
    $ 39.04万
  • 项目类别:
Imaging and Surgery Core
影像和手术核心
  • 批准号:
    10674672
  • 财政年份:
    2022
  • 资助金额:
    $ 39.04万
  • 项目类别:
Mechanisms that alter lymphatic transport in inflammatory bowel disease
改变炎症性肠病淋巴运输的机制
  • 批准号:
    10565928
  • 财政年份:
    2022
  • 资助金额:
    $ 39.04万
  • 项目类别:
Interplay between meningeal lymphatics, high-density lipoproteins and border macrophages in cerebral amyloid angiopathy
脑淀粉样血管病中脑膜淋巴管、高密度脂蛋白和边界巨噬细胞之间的相互作用
  • 批准号:
    10674681
  • 财政年份:
    2022
  • 资助金额:
    $ 39.04万
  • 项目类别:
Defining the lymphatic basis of protein losing enteropathy after Fontan palliation or inflammatory gut disease
定义 Fontan 姑息治疗或炎症性肠道疾病后蛋白质丢失性肠病的淋巴基础
  • 批准号:
    10325733
  • 财政年份:
    2021
  • 资助金额:
    $ 39.04万
  • 项目类别:
Defining the lymphatic basis of protein losing enteropathy after Fontan palliation or inflammatory gut disease
定义 Fontan 姑息治疗或炎症性肠道疾病后蛋白质丢失性肠病的淋巴基础
  • 批准号:
    10661777
  • 财政年份:
    2021
  • 资助金额:
    $ 39.04万
  • 项目类别:
Gut region-specific mechanisms that limit dissemination of microbial signals from the intestine
限制肠道微生物信号传播的肠道区域特异性机制
  • 批准号:
    10283039
  • 财政年份:
    2021
  • 资助金额:
    $ 39.04万
  • 项目类别:
Gut region-specific mechanisms that limit dissemination of microbial signals from the intestine
限制肠道微生物信号传播的肠道区域特异性机制
  • 批准号:
    10665044
  • 财政年份:
    2021
  • 资助金额:
    $ 39.04万
  • 项目类别:
DIFFERENTIATION AND FUNCTION OF MONOCYTES AND MACROPHAGES
单核细胞和巨噬细胞的分化和功能
  • 批准号:
    10158696
  • 财政年份:
    2020
  • 资助金额:
    $ 39.04万
  • 项目类别:
Cellular and spatial mechanisms underlying how inflammatory cytokines impact postprandial glucose responses in health and disease
炎症细胞因子如何影响健康和疾病中餐后葡萄糖反应的细胞和空间机制
  • 批准号:
    10064841
  • 财政年份:
    2020
  • 资助金额:
    $ 39.04万
  • 项目类别:

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Agonist-GPR119-Gs复合物的结构生物学研究
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