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

NEUROBIOLOGY OF AGING

卷:44

Article

Norden, Diana M.¹  Trojanowski, Paige J.¹  Walker, Frederick R.²  Godbout, Jonathan P.^1,3,4 

[1] Ohio State Univ, Dept Neurosci, Columbus, OH 43210 USA

[2] Univ Newcastle, Sch Pharm & Biomed Sci, Callaghan, NSW 2308, Australia

[3] Ohio State Univ, Ctr Brain & Spinal Cord Repair, Columbus, OH 43210 USA

[4] Ohio State Univ, Inst Behav Med Res, Columbus, OH 43210 USA

关键词: Astrocyte;    Microglia;    Aging;    Neuroinflammation;    Interleukin-10;    TGF-beta;   

DOI  :  10.1016/j.neurobiolaging.2016.04.014

来源: Elsevier

【 摘 要 】

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 beta 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 beta 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. (C) 2016 Elsevier Inc. All rights reserved.

【 授权许可】

Free