Implication of the IL-10/TGFβ Pathway in Age-Associated Neuroinflammation
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Date
2020-05
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The Ohio State University
Abstract
Peripheral infections induce prolonged and exaggerated neuroinflammatory responses in the aged brain that result in cognitive impairment, neuropsychiatric complications and ultimately, increased mortality rates. Impaired bidirectional communication between microglia and astrocytes, the primary immune cells of the brain, contributes to a pro-inflammatory microglial phenotype that underlies exacerbated neuroinflammation and sickness behavior. Microglia signal to astrocytes with interleukin (IL)-10; in response, astrocytes regulate microglia with transforming growth factor beta (TGFβ). Aged microglia produce increased levels of both pro- and anti-inflammatory cytokines. However, aged astrocytes exhibit decreased IL-10 receptor (IL-10Rα) expression and are less sensitive to IL-10 signaling. In turn, aged astrocytes produce less TGFβ and are unable to properly attenuate microglial inflammation.
We hypothesized that age-associated impairment of this signaling pathway underlies the peripherally induced exaggerated sickness response. Cre/lox recombination was used to cross Aldh1l1-CreERT2 and Il10raflox/flox mouse lines to conditionally knockout astrocytic Il10ra upon tamoxifen administration and recapitulate an aged-like phenotype. Concurrently, adeno-associated virus (AAV)-mediated gene therapy was administered directly to astrocytes in the hippocampus of aged mice to augment TGFβ signaling. Mice were administered lipopolysaccharide to induce a peripheral immune response. Social behavioral testing was followed by characterization of glial mRNA via real-time polymerase chain reaction (qPCR).
Knockout of Il10ra in adult astrocytes impaired astrocytic TGFβ-mediated attenuation of microglia, inducing prolonged and exaggerated neuroinflammation and depressive-like sickness behavior. In aged mice, virally augmenting astrocytic TGFβ ameliorated age-associated exaggeration of inflammatory sickness response to peripheral immune challenge. Together these data implicate this pathway as a potential therapeutic target in resolving cognitive and neuropsychiatric complications stemming from peripheral infections in the elderly.
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Keywords
neuroinflammation, microglia, astrocyte, aging, gene therapy, IL-10