Insensitivity of Astrocytes to Interleukin-10 Signaling following Peripheral Immune Challenge Results in Prolonged Microglial Activation in the Aged Brain

Abstract 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...

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Bibliographic Details
Published in:Neurobiology of aging 2016-08, Vol.44, p.22-41
Main Authors: Norden, Diana M, Trojanowski, Paige J, Walker, Frederick R, Godbout, Jonathan P
Format: Article
Language:English
Subjects:
Aging
Aging - immunology
Aging - pathology
Amino Acid Transport System X-AG - metabolism
Animals
Astrocyte
Astrocytes - immunology
Astrocytes - metabolism
Brain - metabolism
Cells, Cultured
Coculture Techniques
Glial Fibrillary Acidic Protein - metabolism
Interleukin-10
Interleukin-10 - physiology
Interleukin-10 Receptor alpha Subunit - metabolism
Internal Medicine
Lipopolysaccharides - immunology
Mice, Inbred BALB C
Mice, Inbred C57BL
Microglia
Microglia - immunology
Microglia - metabolism
Neuroinflammation
Neurology
Signal Transduction - physiology
TGF-beta
Transforming Growth Factor beta - metabolism
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Summary:Abstract 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.
ISSN:0197-4580
1558-1497
DOI:10.1016/j.neurobiolaging.2016.04.014