RON Receptor Tyrosine Kinase, a Negative Regulator of Inflammation, is Decreased During SIV Associated Central Nervous System Disease. (168.33)

Abstract

Abstract Expressed on tissue resident macrophages, the receptor tyrosine kinase, RON, functions to maintain inflammation homeostatisis by activating genes that promote wound repair and resolve inflammation; while repressing genes that perpetuate tissue damage. Chronic HIV infection is associated with dysregulated inflammation that contributes to organ diseases, and we hypothesize that altered RON expression contributes to the development of HIV associated CNS disease. We developed a tractable in vitro model using macrophages isolated from human tonsil; these cells express CD14, CD16, CD206, CCR5, and RON. Treatment with RON ligand induced arginase and inhibited HIV and IL-12p40. Following infection, RON expression was down-regulated. We utilized a well characterized SIV model in macaques to explore the temporal regulation of RON in the brain. Following prolonged SIV infection, RON expression decreased. RON was maintained in animals that did not develop CNS disease and was reduced in macaques that demonstrated CNS disease symptoms. Arginase expression was reduced during late infection whereas expression of the inflammatory genes, interleukin 12p40 and TNFα was elevated. Our data support a model in which during acute SIV infection in the brain, active inflammation is controlled by RON, however, following prolonged infection, RON expression is decreased, genes that quell inflammation are repressed, and inflammatory mediators are induced to directly promote CNS disease.