Insensitivity of astrocytes to interleukin 10 signaling following peripheral immune challenge results in prolonged microglial activation in the aged brain.
Insensitivity of astrocytes to interleukin 10 signaling following peripheral immune challenge results in prolonged microglial activation in the aged brain.
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DOI：
10.1016/j.neurobiolaging.2016.04.014
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发表时间：
2016-08
影响因子：
4.2
通讯作者：
Godbout JP
中科院分区：
文献类型：
--
作者：
Norden DM;Trojanowski PJ;Walker FR;Godbout JP
Immune-activated microglia from aged mice produce exaggerated levels of cytokines. Despite high levels of microglial 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 GFAP, 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). Following in vivo LPS 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 TGFβ and resolve microglial activation. Additionally, adult astrocytes reduced microglial activation when co-cultured ex vivo, while aged astrocytes did not. Consistent with the aging studies, IL-10RKO astrocytes did not augment TGFβ 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.
