Activated microglia from aged mice are less sensitive to anti-inflammatory feedback from IL-4

Poster Division: Biological Sciences: 3rd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)Aging is associated with increased inflammatory conditions both peripherally and centrally. Our lab has previously shown that microglia, innate immune cells of the central nervous system, become primed and reactive as a function of age. Following an inflammatory stimulus these primed microglia show exaggerated and prolonged activation associated with an extended sickness response and induction of depressive-like behavior. The purpose of this study was to identify a mechanistic cause for prolonged microglial activation following immune challenge. We report that following a peripheral injection of LPS, microglia from adult mice upregulate both inflammatory (M1) and anti-inflammatory (M2c) gene expression, extending our knowledge of the M2b monocyte phenotype. Furthermore, we demonstrate that activated microglia from aged mice show exaggerated expression of M1, M2a, and M2c related genes, rather than a definitive shift towards M1. Protein expression of the receptors for IL-10 (IL-10R1) and IL-4 (IL-4Rα) were assessed on microglia of adult mice following treatment with LPS. Microglia showed marked upregulation of IL-4Rα after LPS treatment, whereas expression of IL-10R1 did not change. Furthermore, activated microglia from aged mice failed to upregulate IL-4Rα. Treatment of activated microglia ex vivo with IL-4 promoted a down-regulation of M1 related gene, inducible nitric oxide synthase (iNOS) and an upregulation of M2 related gene, Arginase I (Arg) following LPS treatment in adult mice. Activated microglia from aged mice, however, maintained high levels of iNOS gene expression, though they still promoted Arg expression. Taken together, these results indicate that activated microglia from aged mice show impairments in the receptor and cell signaling pathways necessary for anti-inflammatory feedback from IL-4.A one-year embargo was granted for this item