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

摘要：项目 3 我们的项目揭示了巨噬细胞代谢、储存、提示和时间依赖性的关键作用 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， 组织特异性生态位，例如脂质含量过多，以及浸润骨髓的招募和运输 衍生的免疫细胞，传递信号以激活常驻免疫细胞中的内源信号通路 （例如，脂肪组织巨噬细胞或肝库普弗细胞）定义了可能后果的范围。项目 3 项研究揭示了晚期糖基化终产物受体（RAGE；基因名称 Ager）及其细胞质结构域结合伴侣 DIAPH1 在实质与免疫细胞功能障碍中的作用。项目 该计划项目第一周期的 3 个关键发现包括：(1) 骨髓细胞中 Ager 或 Diaph1 的缺失 显着增加胰岛素抵抗，而不会进一步增加高脂肪饮食喂养小鼠的体重； (2) RAGE/DIAPH1 有助于调节肝脏脂质代谢； (3)巨噬细胞RAGE有助于 干扰素调节因子 7 (IRF7) 的调节； IRF7 在脂质代谢和炎症之间架起桥梁 巨噬细胞； (4) 在喂食诱导非酒精性脂肪性肝炎 (NASH) 饮食的小鼠中，Ager 的髓系缺失 RAGE/DIAPH1 或新型小分子拮抗剂对脂肪变性和纤维化产生复杂的影响。 这些考虑使我们推测 RAGE/DIAPH1 有助于巨噬细胞的调节 新陈代谢；响应组织和线索特异性刺激的分子重新编程；和巨噬细胞内 和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 检验 DIAPH1 通过器官内和器官间脂质调节导致动脉粥样硬化的假设 新陈代谢和炎症； AIM 2 检验 RAGE/DIAPH1/IRF7 解开肝脏脂肪变性的假设 通过调节脂质代谢和浸润性 Mɸs 的动态重编程来抑制 NASH 中的纤维化 驻留库普弗细胞； AIM 3 将检验 RAGE/DIAPH1 有助于心脏代谢的假设 疾病是通过器官间的通讯来实现的。项目 3 和项目 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，由巨噬细胞及其关键的驱动 与实质和非实质生态位特异性细胞的相互作用。补充强化 在人体组织和转录组数据库中进行检查，我们将采用最先进的 RNA 测序， 与战略性利用的空间转录组学相结合，生成并“可视化”全面的图谱 假定的相互作用组和调节器官内和器官间交叉的上游转录调节因子 谈论心脏代谢疾病。这项工作和计划项目对于确定有针对性的和 通过调节失调的巨噬细胞诱发动脉粥样硬化、肥胖和 NASH 的谨慎治疗 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.