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. ? ?
| Lin, Adora A; Wojciechowski, Sara E; Hildeman, David A (2010) Androgens suppress antigen-specific T cell responses and IFN-? production during intracranial LCMV infection. J Neuroimmunol 226:8-19 |
| Lin, Adora A; Tripathi, Pulak K; Sholl, Allyson et al. (2009) Gamma interferon signaling in macrophage lineage cells regulates central nervous system inflammation and chemokine production. J Virol 83:8604-15 |
