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

项目摘要 衰老与增加的肥胖有关，这在许多人中引起低度慢性炎症。 组织，称为“炎症-老化”。这种代谢引发的炎症，又称“元炎症”， 许多与年龄相关的疾病的病理过程，是衰老的标志。宏观经济是一个主要的 免疫介导的炎症。巨噬细胞由促炎性M1和抗炎性M2组成 细胞，其响应于环境线索而动态地极化到M1和M2状态。 巨噬细胞极化在衰老中受损，这有助于炎症-衰老。巨噬细胞抗 炎症重编程具有预防/逆转衰老中的继发性炎症的潜力。但 巨噬细胞极化的调节机制还不清楚。生长激素促分泌素 受体（GHS-R）是已知的营养敏感肠激素生长素释放肽的受体。我们发现全球GHS- R消融可防止肥胖、胰岛素抵抗、脂肪组织炎症和非酒精性 脂肪性肝炎（NASH）。GHS-R在巨噬细胞中高度表达，并且其表达增加， 衰老相反，GHS-R的表达在肝细胞中检测不到，在脂肪细胞中非常低。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性作用。我们的初步数据显示 提示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 （IRS 2）和蛋白激酶Akt。因此，我们假设GHS-R是一个关键的调节因子， 衰老中的巨噬细胞极化。具体而言，GHS-R激活IRS 2-Akt通路， 重新编程巨噬细胞，以促进促炎极化在老化过程中，导致Meta- 脂肪组织和肝脏炎症。阐明GHS-R在糖尿病中的作用及其相关机制， 巨噬细胞重编程和炎症，我们已经产生了骨髓特异性GHS-R敲除， 重新表达的小鼠。将测试以下全面和互补的具体目标：1。确定 GHS-R在巨噬细胞极化中作用及其对脂肪和肝脏继发性炎症的影响 老化（体内研究）; 2.通过评估GHS-R的细胞自主作用来探究细胞机制， 巨噬细胞，以及GHS-R缺陷/再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.阐明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激活胰岛素信号通路，上调合成代谢 糖酵解和下调脂肪酸氧化途径，从而促进促炎性极化。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 可能揭示了一种新的调节机制，将营养传感信号和代谢调节 巨噬细胞中的通路。该提案还将提供“概念验证”证据，以证明 巨噬细胞中的GHS-R将是对抗炎症-衰老的独特而有力的策略。

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.