RAGE, DIAPH1 and IRF7 and Macrophage Dysfunction in Atherosclerosis and Cardiometabolic Disease

摘要：项目3 我们的计划项目已经揭示了巨噬细胞代谢的关键作用，仓库，线索，和时间依赖性 心脏代谢功能障碍发病机制中的分子重编程和器官内运输。在每个 代谢环境，包括动脉粥样硬化斑块、肥胖脂肪组织和肝脏， 组织特异性小生境，如脂质含量过多，以及浸润骨髓的募集和运输- 衍生的免疫细胞，其递送信号以激活驻留免疫细胞中的内源性信号传导途径 (e.g.,脂肪组织巨噬细胞或肝枯否细胞），定义了可能后果的广度。项目 3项研究揭示了晚期糖基化终末产物受体（receptor for advanced glycation end products，基因名称： Ager）及其胞质结构域结合伴侣DIAPH 1在实质与免疫细胞功能障碍中的作用。项目 该项目第1周期的3项关键发现包括：（1）髓系细胞中Ager或Diaph 1的缺失 显著增加胰岛素抵抗，而不进一步增加高脂肪饮食喂养的小鼠的体重;（2） CD 4/DIAPH 1有助于调节肝脏脂质代谢;（3）巨噬细胞CD 4/DIAPH 1有助于调节肝脏脂质代谢。 干扰素调节因子7（IRF 7）的调节; IRF 7在脂质代谢和炎症中起桥梁作用。 巨噬细胞;和（4）在喂食非酒精性脂肪性肝炎（NASH）诱导饮食的小鼠中，Ager的骨髓缺失 或新的小分子拮抗剂，赋予脂肪变性和纤维化复杂的后果。 这些考虑使我们假设，CD 4/DIAPH 1有助于调节巨噬细胞 代谢;响应于组织和线索特异性刺激的分子重编程;和巨噬细胞内 和器官间通讯的作用。我们将追求三个具体目标：目标1将 检验DIAPH 1通过器官内和器官间脂质调节促进动脉粥样硬化的假设 AIM 2检验了以下假设：NAFLD/DIAPH 1/IRF 7不偶联肝脏脂肪变性， 通过调节脂质代谢和浸润性M β细胞的动态重编程， 常驻枯否细胞;和AIM 3将测试的假设，即β 1/DIAPH 1有助于心脏代谢， 通过器官间通讯传播疾病。项目3与项目1-2将确定仓库、提示和 心脏代谢功能障碍的时间介导机制，由巨噬细胞驱动， 与实质和非实质小生境特异性细胞的相互作用。通过补充加强 在人类组织和转录组数据库的检查，我们将采用最先进的RNA测序， 再加上战略性利用的空间转录组学，以产生和“可视化”的全面地图， 假定的相互作用组和上游转录调节因子，调节器官内和器官间的交叉， 心血管代谢紊乱这项工作和方案项目对确定有针对性的和 通过巨噬细胞介导的调节异常的透镜， 代谢器官网络中的通信。

Summary: Project 3 Our Program Project has unveiled key roles for macrophage metabolism, depot-, cue-, and time-dependent molecular re-programming and intraorgan trafficking in the pathogenesis of cardiometabolic dysfunction. In each metabolic setting, including the atherosclerotic plaque, obese adipose tissue and liver, the composition of the tissue-specific niche, such as excess lipid content, and recruitment and trafficking of infiltrating bone marrow- derived immune cells, which deliver signals to activate endogenous signaling pathways in resident immune cells (e.g., adipose tissue macrophages or liver Kupffer cells), defines the breadth of possible consequences. Project 3 studies reveal novel, complex roles for the receptor for advanced glycation end products (RAGE; gene name Ager) and its cytoplasmic domain binding partner, DIAPH1, in parenchymal vs. immune cell dysfunctions. Project 3 key discoveries during Cycle 1 of the Program Project include: (1) deletion of Ager or Diaph1 in myeloid cells significantly increases insulin resistance without further increasing body mass in high fat diet-fed mice; (2) RAGE/DIAPH1 contributes to regulation of hepatic lipid metabolism; (3) macrophage RAGE contributes to regulation of Interferon Regulatory Factor 7 (IRF7); IRF7 bridges lipid metabolism and inflammation in macrophages; and (4) in mice fed a non-alcoholic steatohepatitis (NASH)-inducing diet, myeloid deletion of Ager or novel small molecule antagonists of RAGE/DIAPH1 imparts complex consequences on steatosis and fibrosis. These considerations lead us to hypothesize that RAGE/DIAPH1 contributes to regulation of macrophage metabolism; molecular re-programming in response to tissue- and cue-specific stimuli; and macrophage intra- and interorgan communications in cardiometabolic dysfunction. We will pursue three specific aims: Aim 1 will test the hypothesis that DIAPH1 contributes to atherosclerosis through intra- and interorgan regulation of lipid metabolism and inflammation; AIM 2 test the hypothesis that RAGE/DIAPH1/IRF7 uncouples liver steatosis and fibrosis in NASH through regulation of lipid metabolism and dynamic reprogramming of infiltrating Mɸs and resident Kupffer cells; and AIM 3 will test the hypothesis that RAGE/DIAPH1 contributes to cardiometabolic disease through interorgan communications. Project 3, with Projects 1-2, will identify the depot-, cue- and temporal-mediating mechanisms of cardiometabolic dysfunction, driven by macrophages and, critically, their interactions with parenchymal and non-parenchymal niche-specific cells. Fortified by complementary examinations in human tissues and transcriptome databases, we will employ state-of-the-art RNA sequencing, coupled with strategically-utilized spatial transcriptomics, to generate and “visualize” a comprehensive map of the putative interactome and the upstream transcriptional regulators that regulate intra- and interorgan cross- talk in cardiometabolic disorders. This work and the Program Project hold great promise to identify targeted and prudent therapies in atherosclerosis, obesity and NASH through the lens of dysregulated macrophage-evoked communications in metabolic organ networks.