Insensitivity of astrocytes to interleukin 10 signaling following peripheral immune challenge results in prolonged microglial activation in the aged brain

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• 作者：Diana M. Norden^a ; Paige J. Trojanowski^a ; Frederick R. Walker^b ; Jonathan P. Godbout^a ; ^c ; ^d ; ^{jonathan.godbout@osumc.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Astrocyte ; Microglia ; Aging ; Neuroinflammation ; Interleukin-10 ; TGF-beta
• 刊名：Neurobiology of Aging
• 出版年：2016
• 出版时间：August 2016
• 年：2016
• 卷：44
• 期：Complete
• 页码：22-41
• 全文大小：4924 K

文摘

Immune-activated microglia from aged mice produce exaggerated levels of cytokines. Despite high levels of microglial interleukin (IL)-10 in the aged brain, neuroinflammation was prolonged and associated with depressive-like deficits. Because astrocytes respond to IL-10 and, in turn, attenuate microglial activation, we investigated if astrocyte-mediated resolution of microglial activation was impaired with age. Here, aged astrocytes had a dysfunctional profile with higher glial fibrillary acidic protein, lower glutamate transporter expression, and significant cytoskeletal re-arrangement. Moreover, aged astrocytes had reduced expression of growth factors and IL-10 receptor-1 (IL-10R1). After in vivo lipopolysaccharide immune challenge, aged astrocytes had a molecular signature associated with reduced responsiveness to IL-10. This IL-10 insensitivity of aged astrocytes resulted in a failure to induce IL-10R1 and transforming growth factor β and resolve microglial activation. In addition, adult astrocytes reduced microglial activation when co-cultured ex vivo, whereas aged astrocytes did not. Consistent with the aging studies, IL-10R^KO astrocytes did not augment transforming growth factor β after immune challenge and failed to resolve microglial activation. Collectively, a major cytokine-regulatory loop between activated microglia and astrocytes is impaired in the aged brain.