Age-related impairments in the dynamic regulation of active microglia by astrocytes

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 following systemic immune challenge. Recently we showed that astrocytes of adult mice express the IL-10 receptor (IL-10R) and that IL-10 re-directs active astrocytes to produce TGFbeta, which in turn, attenuates the activation of microglia. Therefore, the purpose of this study was to investigate the degree to which these key cytokine interactions between glia are impaired in the aged brain. Here we report that along with microglia, astrocytes also had a primed morphological profile in aged mice. In addition, aged astrocytes had increased GFAP and vimentin expression, and decreased IL-10R surface expression compared to adults. Following acute immune challenge in vivo, adult astrocytes up-regulated IL-10R and TGFbeta mRNA. Aged astrocytes, however, failed to increase expression of these mediators. This lack of regulation by TGFbeta was associated with decreased TGFbeta signaling and exaggerated expression of pro-inflammatory mediators in aged microglia. Additionally, active microglia cultured ex vivo with adult astrocytes reduced inflammatory markers while those cultured with aged astrocytes did not. In summary, these novel data indicate that astrocytes have an important role in regulating microglia via TGFbeta signaling and that an impaired IL-10 response in aged astrocytes contributes to age-related deficits in the regulation of active microglia.