Insensitivity of astrocytes to interleukin 10 signaling following peripheral immune challenge results in prolonged microglial activation in the aged brain.
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.
Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
Diana M
DM
Norden
Department of Neuroscience, The Ohio State University, Columbus, OH, USA.
Paige J
PJ
Trojanowski
School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, South Wales, Australia.
Frederick R
FR
Walker
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.
Jonathan P
JP
Godbout
D000375:Aging / Q000276:immunology* / Q000473:pathology*; D027322:Amino Acid Transport System X-AG / Q000378:metabolism; D000818:Animals; D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D018920:Coculture Techniques; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D016753:Interleukin-10 / Q000502:physiology*; D053709:Interleukin-10 Receptor alpha Subunit / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000276:immunology* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D027322:Amino Acid Transport System X-AG; D005904:Glial Fibrillary Acidic Protein; D053709:Interleukin-10 Receptor alpha Subunit; D008070:Lipopolysaccharides; D016212:Transforming Growth Factor beta; D016753:Interleukin-10
Aging; Astrocyte; Interleukin-10; Microglia; Neuroinflammation; TGF-beta