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

摘要：项目3 我们的计划项目揭示了巨噬细胞新陈代谢、仓库、线索和时间依赖的关键作用 心脏代谢功能障碍发病机制中的分子重编程和器官内转运。在每一个中 代谢环境，包括动脉粥样硬化斑块、肥胖脂肪组织和肝脏， 组织特有的生态位，如过多的脂肪含量，以及渗透的骨髓的招募和运输- 衍生免疫细胞，传递信号以激活常驻免疫细胞的内源性信号通路 (例如，脂肪组织巨噬细胞或肝脏枯否细胞)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产物受体(RAGE；基因名称)的新的、复杂的作用 AGE)及其胞浆结构域结合伙伴DIAPH1在实质和免疫细胞功能障碍中的作用。项目 计划项目第一周期的3项关键发现包括：(1)髓系细胞中Ager或DIAPH1的缺失 在不进一步增加高脂饮食小鼠体重的情况下显著增加胰岛素抵抗；(2) RAGE/DIAPH1有助于调节肝脏脂代谢；(3)巨噬细胞RAGE有助于 干扰素调节因子7(IRF7)的调节；IRF7桥接脂代谢和炎症反应 巨噬细胞；以及(4)在喂食非酒精性脂肪性肝炎(NASH)诱导饮食的小鼠中，Ager的髓系缺失 或RAGE/DIAPH1的新型小分子拮抗剂对脂肪变性和纤维化造成复杂的后果。 这些考虑导致我们假设RAGE/DIAPH1参与巨噬细胞的调节 新陈代谢；响应组织和线索特异性刺激的分子重新编程；以及巨噬细胞内 心脏代谢功能障碍中的器官间通讯。我们将追求三个具体目标：目标1将 验证DIAPH1通过调节器官内和器官间的脂质而导致动脉粥样硬化的假设 代谢和炎症；目的2检验RAGE/DIAPH1/IRF7解除肝脏脂肪变性和 调节脂代谢和M-ɸ动态重编程在NASH纤维化中的作用 和AIM 3将检验RAGE/DIAPH1有助于心脏代谢的假设 通过器官间通讯传播疾病。项目3，包括项目1-2，将确定站点-、线索-和 心脏代谢功能障碍的时间中介机制，由巨噬细胞驱动，关键是其 与实质细胞和非实质细胞壁龛特异性细胞的相互作用。互补性强 在人体组织和转录组数据库中进行检查，我们将使用最先进的RNA测序， 再加上战略上利用的空间转录，以生成并可视化 推测的相互作用体和上游转录调节因子，调节器官内和器官间的交叉。 谈论心脏新陈代谢障碍。这项工作和计划项目很有希望确定有针对性的和 通过调节失调的巨噬细胞诱导的晶状体对动脉粥样硬化、肥胖和NASH的谨慎治疗 新陈代谢器官网络中的通讯。

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.