IL-1 dependent anorexia during CNS viral infection

描述（由申请人提供）：厌食和体重减轻是癌症、传染病和自身免疫性疾病发病的重要原因。另一方面，肥胖目前是一种日益增长的流行病，并且是美国心脏病和II型糖尿病的主要潜在原因之一。一般来说，这些疾病中能量稳态的调节受到免疫系统产生的因素的影响。能量稳态通常由CNS中调节能量摄入和能量消耗的信号控制。尽管在理解参与食物摄入的正常调节的分子方面取得了重大进展，但在疾病期间免疫/CNS相互作用对这些过程所起的作用还不太清楚。我们和其他人已经报道了在颅内（i.c.）淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染。值得注意的是，这种厌食症的体重减轻需要CD 4 + T细胞，并且在外周LCMV感染后不会发生，表明CNS和免疫系统之间的相互作用导致厌食症。虽然即LCMV感染激发一系列细胞因子，但IL-1信号传导的消除（在IL-1 R缺陷小鼠中遗传地或通过脑室内施用抗IL-1抗体）防止体重减轻和厌食症。该结果表明，IL-1对于LCMV感染后的大鼠体重减轻至关重要。此外，在体重减轻开始时，a-MSH和IL-1蛋白的CNS水平显著增加，而血清瘦素水平与体重减轻无关。基于这些初步观察，我们假设：在LCMV感染中，CNS内细胞产生的IL-1导致α-MSH增加，这对厌食症和体重减轻至关重要。我们将通过以下特定目的中概述的一系列确定的实验来检验该假设：i）鉴定和表征LCMV感染期间CNS中的IL-1产生细胞; ii）鉴定由IL-1调节的在LCMV感染期间引起厌食的分子机制。这些研究的长期目标是确定在厌食症治疗中可能被治疗操纵的分子靶点。

DESCRIPTION (provided by applicant): Anorexia and weight loss are a significant cause of morbidity in cancer, infectious diseases, and autoimmune disease. On the other hand, obesity is currently an increasing epidemic and is one of the leading underlying causes of heart disease and type II diabetes in the United States. In general, the regulation of energy homeostasis in these diseases is influenced by factors produced by the immune system. Energy homeostasis is normally controlled by signals in the CNS that regulate energy intake and energy expenditure. Despite the significant advancements in understanding the molecules involved in normal regulation of food intake, the role played by immune/CNS interactions on these processes during disease is less well understood. We and others have reported a severe anorectic weight loss occurring in mice following intracranial (i.c.) lymphocytic choriomeningitis virus (LCMV) infection. Notably, this anorectic weight loss requires CD4+ T cells and does not occur after peripheral LCMV infection, demonstrating that interactions between the CNS and immune systems cause anorexia. While i.e. LCMV infection elicits an array of cytokines, ablation of IL-1 signaling (either genetically in IL-lR-deficient mice or through intracerebroventricular administration of anti-IL-1 antibody) prevents weight loss and anorexia. This result demonstrates that IL-1 is critical for anorexic weight loss after LCMV infection. Additionally, at the onset of weight loss, CNS levels of a-MSH and IL-1 proteins are significantly increased, whereas serum leptin levels do not correlate with weight loss. Based on these preliminary observations, we hypothesize that: in LCMV infection, IL-1 production by cells within the CNS lead to increased a-MSH, which is critical to the anorexia and weight loss. We will test this hypothesis through a defined series of experiments outlined in the following specific aims, i) To identify and characterize IL-1 producing cells in the CNS during LCMV infection; ii) To identify molecular mechanism(s), regulated by IL-1 that cause anorexia during LCMV infection. The long-term goal of these studies is to identify molecular targets that may be manipulated therapeutically in the treatment of disease anorexia.