132. The role of astrocytes in IL-10 mediated regulation of inflammation within the CNS

Abstract

Activated microglia from aged mice produce exaggerated levels of both pro-and anti-inflammatory cytokines, including interleukin (IL)-10. Despite higher levels of IL-10, microglial activation is prolonged in the aged brain. Astrocytes express the IL-10 receptor and produce cytokines, including TGF β , that attenuate microglial activation. Therefore, to examine the failure of IL-10 to resolve inflammation within the aged brain, we evaluated the sensitivity of microglia and astrocytes to IL-10. We found that in vivo , astrocytes have higher surface expression of IL-10 receptor compared to microglia. In vitro , IL-10 lowered IL-1 β expression in activated astrocytes, and not microglia. Furthermore, IL-10 increased TGF β production in activated astrocytes. TGF β , in turn increased expression of the regulatory receptors CX3CR1 and IL-4R on microglia. In astrocyte and microglia co-cultures, IL-10 decreased IL-1 β expression in microglia and increased IL-4R expression. Blockade of TGF β signaling decreased IL-4R induction and also decreased CX3CR1 expression in microglia co-cultured with astrocytes. Thus, astrocyte production of TGF β plays an important role in regulating immune activated microglia. Next, we examined the inflammatory status of astrocytes in adult and aged mice and found that astrocytes in aged mice had increased GFAP and vimentin expression, and decreased IL-10 receptor surface expression compared to adults. Overall, astrocytes from aged mice are more inflammatory and less sensitive to IL-10, which may negatively affect TGF β production and regulation of microglia in the aged brain.