Leptin as a modulator of glial activity in inflammation

免疫系统和大脑之间的交流是控制我们对入侵病原体做出反应并对其进行有效防御的能力的关键过程。外周免疫介质称为细胞因子(如白介素1)，通过在大脑中的直接作用在这种交流中发挥重要作用。我们以前已经证明，瘦素是这个家族的一个新成员，它主要由脂肪与其质量的比例产生，主要参与通过抑制食欲来控制体重，刺激大脑中细胞因子的产生，并可能在疾病期间扮演新的循环信使的角色。除了抑制食欲，我们还首次报道了瘦素会引起发烧，这是疾病的一个标志，瘦素是人体抵御细菌感染和炎症的防御机制不可或缺的一部分。我们的最新发现表明，这种类似细胞因子的激素在免疫中的作用比最初设想的要复杂得多，它不是直接作用于大脑的炎症靶点，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行动。我们发现，瘦素对这些细胞的作用使它们更有可能对炎症刺激做出有效反应。目前的提案中描述的工作将通过提出这样的假设来研究这一机制，即瘦素在免疫中的作用是大脑中免疫细胞活动的调节器，其中可能包括抗凋亡活性。由于循环中的瘦素水平在多种情况下(如肥胖、厌食症)波动，这种激素在调节大脑中免疫细胞功能方面的作用可能会对神经炎性反应产生广泛的影响。因此，为了解决这一假说，我们将在啮齿动物身上进行体内和体外两种方法，以探索瘦素对脑内小胶质细胞作用的潜在机制，特别是涉及的受体，以及循环中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.