IL-1 dependent anorexia during CNS viral infection

CNS病毒感染期间IL-1依赖性厌食

• 批准号: 7318492
• 负责人: David A Hildeman
• 金额: $ 16.39万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-12-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7318492
• 关键词: ART protein; Ablation; Acquired Immunodeficiency Syndrome; Acute; Affect; Animals; Anorexia; Antibodies; Appetite Depressants; Attenuated; Autoimmune Diseases; Bacterial Infections; Biological Response Modifiers; Body Weight decreased; Bone Marrow; CD4 Positive T Lymphocytes; CRH gene; Cells; Central Nervous System Viral Diseases; Chimera organism; Clinical; Communicable Diseases; Complex; Corticotropin-Releasing Hormone; Data; Disease; Dose; Eating; Endocrine system; Energy Intake; Energy Metabolism; Epidemic; Exhibits; Food Intake Regulation; Galanin; Goals; Hand; Heart Diseases; Homeostasis; Hunger; Hypothalamic structure; Immune; Immune system; In Situ; Infection; Interleukin-1; Interleukin-1 alpha; Knowledge; Lead; Leptin; Lipopolysaccharides; Lymphocytic choriomeningitis virus; Malignant Neoplasms; MeSH Thesaurus; Melanocortin 4 Receptor; Melanocyte stimulating hormone; Messenger RNA; Molecular; Molecular Target; Morbidity - disease rate; Mus; Neuraxis; Neurons; Neuropeptides; Non-Insulin-Dependent Diabetes Mellitus; Obesity; POMC gene; Peripheral; Personal Satisfaction; Play; Process; Production; Proteins; Regulation; Relative (related person); Reporting; Research Personnel; Role; Role playing therapy; Satiation; Series; Serum; Signal Transduction; Testing; United States; Viral; Virus Diseases; base; body system; cytokine; gastrointestinal system; neuropeptide Y; prevent; programs; research study; response

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.

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，肥胖目前正在日益流行，并且是美国心脏病和二型糖尿病的主要原因之一。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。能量稳态通常由中枢神经系统中调节能量摄入和能量消耗的信号控制。尽管在理解食物摄入正常调节所涉及的分子方面取得了重大进展，但疾病期间免疫/中枢神经系统相互作用在这些过程中所发挥的作用尚不清楚。我们和其他人报告了颅内（i.c）淋巴细胞脉络膜脑膜炎病毒（LCMV）感染后小鼠出现严重的厌食体重减轻。值得注意的是，这种厌食性体重减轻需要 CD4+ T 细胞，并且在外周 LCMV 感染后不会发生，这表明中枢神经系统和免疫系统之间的相互作用会导致厌食。即，虽然LCMV感染引发一系列细胞因子，但IL-1信号传导的消除(在IL-1R缺陷小鼠中通过遗传或通过脑室内施用抗IL-1抗体)可防止体重减轻和厌食。这一结果表明，IL-1 对于 LCMV 感染后厌食症体重减轻至关重要。此外，在体重减轻开始时，中枢神经系统中α-MSH和IL-1蛋白的水平显着升高，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，中枢神经系统内细胞产生的 IL-1 导致 a-MSH 增加，这对厌食和体重减轻至关重要。我们将通过一系列明确的实验来检验这一假设，这些实验概述了以下具体目标： i) 鉴定和表征 LCMV 感染期间中枢神经系统中产生 IL-1 的细胞； ii) 确定在 LCMV 感染期间由 IL-1 调节导致厌食的分子机制。这些研究的长期目标是确定可用于治疗厌食症的分子靶标。

项目成果

Androgens suppress antigen-specific T cell responses and IFN-γ production during intracranial LCMV infection.

• DOI: 10.1016/j.jneuroim.2010.05.026
• 发表时间: 2010-09-14
• 期刊: Journal of neuroimmunology
• 影响因子: 3.3
• 作者: Lin AA;Wojciechowski SE;Hildeman DA
• 通讯作者: Hildeman DA