Leptin as a modulator of glial activity in inflammation

免疫系统和大脑之间的沟通是一个关键的过程，控制着我们对入侵病原体做出反应和建立有效防御反应的能力。被称为细胞因子（例如白细胞介素-1）的外周免疫介质通过大脑中的直接作用在这种通信中发挥重要作用。我们以前已经表明，这个家族的一个新成员，瘦素，主要由脂肪按其质量比例产生，主要通过抑制食欲来控制体重，刺激大脑中细胞因子的产生，并可能在疾病期间作为新的循环信使。除了抑制食欲外，我们还首次报道了瘦素诱导发热，这是疾病的标志，瘦素是身体抵抗细菌感染和炎症的防御机制的组成部分。我们的最新发现表明，这种细胞因子样激素在免疫中的作用比最初设想的更复杂，而不是直接作用于炎症的大脑靶点，而是通过调节大脑中常驻免疫细胞（即小胶质细胞）的准备状态来促进其他炎症分子的作用。我们已经发现，瘦素对这些细胞的作用使它们更有可能有效地对炎症刺激做出反应。在目前的建议中所描述的工作将调查这一机制，提出的假设，瘦素在免疫中的作用是在大脑中的免疫细胞活性，其中可能包括抗凋亡活性的调制器。由于循环中的瘦素水平在多种情况下（例如肥胖，厌食症）波动，因此这种激素在调节大脑中免疫细胞功能中的作用可能对神经炎症反应具有广泛的影响。因此，为了解决这一假设，我们将在啮齿动物体内和体外进行方法，以探索负责瘦素对脑中小胶质细胞的作用的潜在机制，特别是关注所涉及的受体以及循环瘦素水平的波动如何影响这些作用。

Communication between the immune system and the brain is a critical process governing our ability to respond to and mount an effective defense response against invading pathogens. Peripheral immune mediators known as cytokines (e.g. interleukin-1) play an important role in this communication through direct actions in the brain. We have shown previously that a new member of this family, leptin, which is mainly produced by fat in proportion to its mass, and is involved principally in controlling body weight by suppressing appetite, stimulates the production of cytokines in the brain and may act as a new circulating messenger during disease. In addition to inhibiting appetite we also reported, for the first time, that leptin induces fever, which is a hallmark for disease and that leptin is integral to the body's defense mechanisms against bacterial infection and inflammation. Our latest discoveries indicate that the role of this cytokine like hormone in immunity is more complex than first envisaged and rather than acting directly on brain targets of inflammation it instead facilitates the action of other inflammatory molecules by regulating the state of readiness of the resident immune cells in the brain, namely microglia. We have discovered that the action of leptin on these cells makes them more likely to respond to an inflammatory stimulus efficiently. The work described in the current proposal will investigate this mechanism by posing the hypothesis that the role of leptin in immunity is that of a modulator of immune cell activity in the brain, which may include anti-apoptotic activity. Because circulating leptin levels fluctuate across a multitude of conditions (e.g. obesity, anorexia) a role for this hormone in modulating immune cell function in the brain could have wide-ranging implications for neuro-inflammatory responses. Thus to address this hypothesis we will conduct both in vivo and in vitro approaches in rodents to explore the underlying mechanisms responsible for the actions of leptin on microglial cells in the brain and in particular focus on the receptors involved and on how the fluctuation of circulating leptin levels can influence these effects.