Macrophage inflammasome activation and the mechanism of lipolysis resistance in aged adipose

项目摘要 在老年人中观察到的内脏肥胖和炎症增加与以下风险增加相关： 代谢性疾病，如糖尿病和动脉粥样硬化。此外，炎症和代谢性疾病是 与患痴呆症和神经退行性疾病（包括阿尔茨海默氏症）的风险增加有关 疾病（AD）。一个主要的重叠途径驱动代谢和阿尔茨海默病是NLRP 3 炎症体途径，其在暴露于以下物质后在髓样和巨噬细胞样细胞中被激活： 广泛的损伤相关分子模式，如脂肪酸和淀粉样蛋白β（Aβ）。 组织驻留巨噬细胞控制在衰老过程中被破坏的稳态功能。我们的数据显示 脂肪巨噬细胞转录变化导致老年内脏脂肪组织中脂肪分解受损。我们 鉴定了巨噬细胞表达的生长分化因子（GDF）-3，TGFβ家族的一员， 脂肪脂解的负调节剂和NLRP 3炎性体活化和衰老病理学的驱动剂。 我们正在进行的项目研究了巨噬细胞表达的GDF 3在增加炎症中的作用， 衰老和纤维化以加重老年脂肪组织中的组织功能。具体目标， 该项目的内容包括（1）确定GDF 3如何增加NLRP 3炎性小体激活 和脂解抗性，（2）表征衰老的巨噬细胞，然后确定GDF 3是否驱动 脂肪组织免疫细胞中的衰老，以及（3）鉴定GDF 3是否是ECM产生所需的， 老年脂肪纤维化增加。 Aβ激活NLRP 3炎性体驱动小胶质细胞炎症、Aβ病理学和神经认知 损伤在本补充中，我们建议研究GDF 3作为Nlrp 3炎性小体驱动的活化剂。 神经炎症和脑淀粉样蛋白病理学。在意想不到的发现中，TGF β/GDF信号通路和 GDF 3蛋白在AD患者中减少，可能是通过限制神经发生。因此将 这对于测试GDF 3缺乏是否调节特定细胞中的炎性小体激活至关重要。以识别是否 GDF 3控制炎性小体活化，一种广泛使用的AD转基因小鼠模型（5xFAD小鼠）， 表达GDF 3或GDF 3缺乏的患者将用于评估神经炎症、AD病理学和认知功能。 功能作为体内研究的补充，我们研究了来自于神经胶质细胞的原代小胶质细胞和神经元中的炎性小体激活。 将在存在或不存在Aβ的情况下评价GDF 3表达或缺陷动物。所有这些 项目将研究GDF 3缺乏在代谢疾病期间与年龄相关的炎性小体激活， 老年痴呆症该项目非常适合产生出版物和初步数据， 研究AD病理学中GDF 3-NLRP 3炎性小体轴的额外资金

Project Summary Increased visceral adiposity and inflammation seen in the elderly are associated with elevated risk for metabolic diseases, such as diabetes and atherosclerosis. Moreover, inflammaging and metabolic disease are correlated with increased risk to develop dementia and neurodegenerative diseases including Alzheimer’s disease (AD). One major overlapping pathway driving both metabolic and Alzheimer’s disease is the NLRP3 inflammasome pathway, which becomes activated in myeloid and macrophage-like cells following exposure to a wide range of damage associated molecular patterns, like fatty acids and amyloid-beta (Aβ). Tissue resident macrophages control homeostatic functions that are disrupted during aging. Our data reveals adipose macrophage transcriptional changes lead to impaired lipolysis in aged visceral adipose tissue. We identified macrophage-expressed growth differentiation factor (GDF)-3, a member of the TGFβ family, as a negative regulator of adipose lipolysis and driver of NLRP3 inflammasome activation and aging-pathologies. Our ongoing project examines the role for macrophage-expressed GDF3 in increasing inflammation, senescence and fibrosis to aggravate tissue functioning in the aged adipose tissue. The specifics aims, which are unchanged, of this project include (1) determine how GDF3 increases NLRP3 inflammasome activation and lipolysis resistance, (2) characterize senescent macrophages and then determine whether GDF3 drives senescence in adipose tissue immune cells, and (3) identify whether GDF3 is required for ECM production and increased fibrosis in aged adipose. Aβ activates the NLRP3 inflammasome driving microglial inflammation, Aβ-pathology and neurocognitive impairments. In this supplement we propose to investigate GDF3 as an activator of Nlrp3 inflammasome-driven neuroinflammation and cerebral amyloid pathology. In unexpected findings, TGFb/GDF signaling pathway and GDF3 protein are reduced in human patients with AD, potentially by limiting neurogenesis. Thus it will be critical to test whether GDF3-deficiency regulates inflammasome activation in specific cells. To identify whether GDF3 controls inflammasome activation, a widely used transgenic mouse model of AD, (5xFAD mice), expressing or with GDF3-deficiency will be used to evaluate neuroinflammation, AD-pathology and cognitive function. To complement in vivo studies, inflammasome activation in primary microglia and neurons from GDF3-expressing or deficient animals will be evaluated in the presence or absence of Aβ. Together, these projects will study GDF3-deficiency in age-related inflammasome activation during metabolic disease and Alzheimer’s disease. This project is well-situated to generate publications and preliminary data supporting additional funding for investigating the GDF3-NLRP3 inflammasome axis in AD-pathology