Nutrient-sensing GHS-R in macrophage reprogramming and inflamm-aging

巨噬细胞重编程和炎症衰老中的营养感应 GHS-R

• 批准号: 10425305
• 负责人: YUXIANG SUN
• 金额: $ 30.6万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10425305
• 关键词: Ablation; Adipocytes; Adipose tissue; Age; Aging; Anti-Inflammatory Agents; Attenuated; Biological Assay; Biological Response Modifiers; Bone Marrow; Cells; Characteristics; Chronic; Coculture Techniques; Cues; Data; Diabetes Mellitus; Disease; Elderly; Exhibits; Flow Cytometry; Genes; Genus Hippocampus; Glycolysis; Goals; Hepatic; Hepatocyte; Hormones; IRS2 gene; Impairment; Inflammaging; Inflammation; Inflammatory; Insulin; Insulin Resistance; Insulin Signaling Pathway; Knock-out; Light; Link; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolic syndrome; Metabolism; Mitochondria; Molecular; Morphology; Mus; Myelogenous; Obesity; Pathogenesis; Pathologic Processes; Pathway interactions; Peritoneal; Peritoneal Macrophages; Phenotype; Play; Protein Kinase; Regulatory Pathway; Respiration; Role; Signal Transduction; Steatohepatitis; Testing; Thinness; Tissues; Validation; antagonist; detection of nutrient; diet-induced obesity; dietary; extracellular; fatty acid oxidation; fatty liver disease; ghrelin; growth hormone secretagogue receptor; in vivo; insulin mediators; insulin receptor substrate-2 protein; insulin signaling; knock-down; macrophage; middle age; nonalcoholic steatohepatitis; novel; paracrine; prevent; receptor; receptor expression; response

Project Summary Aging is associated with increased adiposity, that induces low grade chronic inflammation in many tissues, termed “inflamm-aging”. This metabolically-triggered inflammation, aka "meta-inflammation", underlies pathological processes of many age-associated diseases and is a hallmark of aging. Macrophages are a major immune-mediator of meta-inflammation. Macrophages consist of pro-inflammatory M1 and anti-inflammatory M2 cells, which undergo dynamically polarization to either M1 and M2 state in response to environmental cues. Macrophage polarization is impaired in aging, which contributes to inflamm-aging. Macrophage anti- inflammatory reprogramming has potential to prevent/reverse meta-inflammation in aging. However, the regulatory mechanisms of macrophage polarization are not well understood. Growth hormone secretagogue receptor (GHS-R), is a known receptor for nutrient-sensing gut hormone ghrelin. We have found that global GHS- R ablation protects against obesity, insulin resistance, adipose tissue inflammation and nonalcoholic steatohepatitis (NASH) in aging. GHS-R is highly expressed in macrophages and its expression increases in aging. In contrast, GHS-R expression is undetectable in hepatocytes and very low in adipocytes. Our gene knockdown study indicates that GHS-R has cell-autonomous effects in macrophages. Our preliminary data have suggested that GHS-R deletion down-regulates key insulin signaling mediators insulin receptor substrate-2 (IRS2) and protein kinase Akt in macrophages. Hence, we hypothesize that GHS-R is a key regulator of macrophage polarization in aging. Specifically, GHS-R activates the IRS2-Akt pathway to metabolically reprogram macrophages to promote pro-inflammatory polarization during aging, leading to meta- inflammation in adipose tissues and liver. To unravel the roles and pertinent mechanisms of GHS-R in macrophage reprogramming and meta-inflammation, we have generated myeloid-specific GHS-R knockout and re-expressing mice. The following comprehensive and complementary Specific Aims will be tested: 1. Determine the role of GHS-R in macrophage polarization, and its effect on adipose and hepatic meta-inflammation during aging (in vivo studies); 2. Interrogate the cellular mechanisms by assessing cell-autonomous effect of GHS-R in macrophages, and paracrine effect of GHS-R deficient/re-expressing macrophages on adipocytes and hepatocytes (ex vivo studies); 3. Delineate molecular mechanisms by which GHS-R regulates macrophage polarization. We anticipate that during aging, GHS-R activates insulin signaling pathway to upregulate anabolic glycolysis and down-regulate fatty acid oxidation pathways, thus promoting pro-inflammatory polarization. This proposal will shed light on a new paradigm for metabolic reprogramming of macrophages during aging, and will likely uncover a novel regulatory mechanism linking nutrient sensing signaling and metabolic regulatory pathways in macrophages. This proposal will also provide “proof-of-concept” evidence for whether targeting GHS-R in macrophages would be a unique and powerful strategy for combating inflamm-aging.

项目概要 衰老与肥胖增加有关，肥胖会导致许多人出现轻度慢性炎症。 组织，称为“炎症老化”。这种代谢引发的炎症，又名“元炎症”，是 许多与年龄相关的疾病的病理过程，是衰老的标志。巨噬细胞是主要的 元炎症的免疫介质。巨噬细胞由促炎M1和抗炎M2组成 细胞根据环境信号动态极化至 M1 和 M2 状态。 巨噬细胞极化在衰老过程中受损，从而导致炎症衰老。巨噬细胞抗 炎症重编程有可能预防/逆转衰老过程中的元炎症。然而， 巨噬细胞极化的调节机制尚不清楚。生长激素促分泌素 受体（GHS-R）是一种已知的营养感应肠道激素胃饥饿素受体。我们发现全球 GHS- R 消融可预防肥胖、胰岛素抵抗、脂肪组织炎症和非酒精性 衰老过程中的脂肪性肝炎（NASH）。 GHS-R 在巨噬细胞中高表达，并且在 老化。相比之下，GHS-R 表达在肝细胞中检测不到，而在脂肪细胞中表达非常低。我们的基因 敲低研究表明 GHS-R 在巨噬细胞中具有细胞自主效应。我们的初步数据有 表明 GHS-R 缺失下调关键胰岛素信号传导介质胰岛素受体底物-2 (IRS2) 和巨噬细胞中的蛋白激酶 Akt。因此，我们假设 GHS-R 是 衰老过程中巨噬细胞的极化。具体来说，GHS-R 激活 IRS2-Akt 途径以代谢 重新编程巨噬细胞以促进衰老过程中的促炎性极化，从而导致元- 脂肪组织和肝脏的炎症。揭示 GHS-R 在中枢神经系统中的作用和相关机制 巨噬细胞重编程和元炎症，我们已经产生了骨髓特异性 GHS-R 敲除和 重新表达小鼠。将测试以下全面且互补的具体目标： 1. 确定 GHS-R 在巨噬细胞极化中的作用及其对脂肪和肝脏元炎症的影响 衰老（体内研究）； 2. 通过评估 GHS-R 的细胞自主效应来探究细胞机制 巨噬细胞，以及 GHS-R 缺陷/重新表达巨噬细胞对脂肪细胞的旁分泌作用 肝细胞（离体研究）； 3. 描述GHS-R调节巨噬细胞的分子机制 极化。我们预计在衰老过程中，GHS-R 会激活胰岛素信号通路以上调合成代谢 糖酵解和下调脂肪酸氧化途径，从而促进促炎极化。这 该提案将揭示衰老过程中巨噬细胞代谢重编程的新范式，并将 可能会发现一种连接营养传感信号和代谢调节的新调节机制 巨噬细胞中的通路。该提案还将提供“概念验证”证据，证明是否针对 巨噬细胞中的 GHS-R 将是对抗炎症衰老的独特而强大的策略。