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

Autor: Norden DM; Department of Neuroscience, The Ohio State University, Columbus, OH, USA., Trojanowski PJ; Department of Neuroscience, The Ohio State University, Columbus, OH, USA., Walker FR; School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, South Wales, Australia., Godbout JP; Department of Neuroscience, The Ohio State University, Columbus, OH, USA; Center for Brain and Spinal Cord Repair, The Ohio State University, Columbus, OH, USA; Institute for Behavioral Medicine Research, The Ohio State University, Columbus, OH, USA. Electronic address: jonathan.godbout@osumc.edu.
Jazyk: angličtina
Zdroj: Neurobiology of aging [Neurobiol Aging] 2016 Aug; Vol. 44, pp. 22-41. Date of Electronic Publication: 2016 Apr 27.
DOI: 10.1016/j.neurobiolaging.2016.04.014
Abstrakt: 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.
(Copyright © 2016 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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