Role of GDF15 in the Regulation of Host Tolerance to Inflammation

项目概要 生长和分化因子 15 (GDF15) 在几乎所有炎症条件下均被高度诱导 人类，包括脓毒症、癌症和自身免疫，但其在炎症反应中的作用已被证实 不清楚。该提案旨在了解生长和分化因子 15 (GDF15) 在 介导脓毒症的保护作用。 该提议的初步数据表明，GDF15 是在急性炎症模型中特异性诱导的。 感染/炎症，但不是其他环境应激条件，并达到纳克水平 循环。 GDF15 受体，神经胶质细胞衍生的神经营养因子受体 α 样 (GFRAL)， 仅在后脑中发现并且不是由炎症引起的。 GDF15的封锁导致死亡率增加 脓毒症的多种模型，包括脂多糖 (LPS)、盲肠结扎穿刺 (CLP)、Poly(I:C) 和 流感。相反，较晚施用重组 GDF15 会产生保护作用。 GDF15 抑制没有 影响炎症程度或病原体控制。然而，GDF15 封锁导致了 小鼠切换至氧化磷酸化状态的能力。酮血症或血浆没有差异 游离脂肪酸，但循环血浆甘油三酯显着降低。我们还发现封锁 GDF15 导致心脏毒性增强，但总体血流动力学控制没有差异。因此，GDF15 是 组织保护激素。该提案旨在测试 GDF15 是一种产生的适应性细胞因子的观点 巨噬细胞响应急性炎症，通过控制甘油三酯介导心脏保护作用 通过交感神经支配进行新陈代谢。

PROJECT SUMMARY Growth and Differentiation Factor 15 (GDF15) is highly induced in virtually all inflammatory conditions in humans, including sepsis, cancer and autoimmunity, but its role in the inflammatory response has been unclear. This proposal seeks to understand the role of Growth and Differentiation Factor 15 (GDF15) in mediating protection in sepsis. Preliminary data for this proposal reveals that GDF15 is induced specifically in models of acute infection/inflammation but not other environmental stress conditions and achieves nanogram levels in circulation. The GDF15 receptor, glial cell-lone derived neurotrophic factor receptor alpha-like (GFRAL), was found only in the hindbrain and not induced by inflammation. Blockade of GDF15 led to enhanced mortality in multiple models of sepsis, including lipopolysaccharide (LPS), cecal-ligation puncture (CLP), Poly(I:C), and influenza. Conversely, late administration of recombinant GDF15 led to protection. GDF15 inhibition did not affect inflammatory magnitude or pathogen control. However, GDF15 blockade led to an impairment in the ability of mice to switch to an oxidative phosphorylation state. There was no difference in ketonemia or plasma free fatty acids but a significant decrease in circulating plasma triglycerides. We also found that blockade of GDF15 led to enhanced cardiotoxicity, without a difference in overall hemodynamic control. Thus, GDF15 is a tissue protective hormone. This proposal seeks to test the idea that GDF15 is an adaptive cytokine produced by macrophages in response to acute inflammation, which mediates cardioprotection by controlling triglyceride metabolism via sympathetic innervation.