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

Neurobiol Aging. 2016 Aug;44:22-41. doi: 10.1016/j.neurobiolaging.2016.04.014. Epub 2016 Apr 27.


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.

Keywords: Aging; Astrocyte; Interleukin-10; Microglia; Neuroinflammation; TGF-beta.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging / immunology*
  • Aging / pathology*
  • Amino Acid Transport System X-AG / metabolism
  • Animals
  • Astrocytes / immunology*
  • Astrocytes / metabolism*
  • Brain / metabolism*
  • Cells, Cultured
  • Coculture Techniques
  • Glial Fibrillary Acidic Protein / metabolism
  • Interleukin-10 / physiology*
  • Interleukin-10 Receptor alpha Subunit / metabolism
  • Lipopolysaccharides / immunology
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Microglia / immunology*
  • Microglia / metabolism*
  • Signal Transduction / physiology*
  • Transforming Growth Factor beta / metabolism


  • Amino Acid Transport System X-AG
  • Glial Fibrillary Acidic Protein
  • Interleukin-10 Receptor alpha Subunit
  • Lipopolysaccharides
  • Transforming Growth Factor beta
  • Interleukin-10