Microglia and astrocytes are key cells that recognize, interpret, propagate and regulate immune responses. In the elderly, peripheral infections can trigger delirium and behavioral disturbances. Moreover, ongoing inflammatory processes in the elderly are associated with depressive-like complications. These complications are not a normal part of aging and negatively affect quality of life and life-span. The cause of this altered communication between the immune system and the brain with age is unclear, but our data points to an impaired regulation of microglia. We have reported that microglia from aged mice are primed and become hyperactive following a peripheral immune challenge with lipopolysaccharide (LPS). Aged microglia produce amplified levels of both inflammatory (IL-1) and anti-inflammatory (IL-10) cytokines. Although IL-10 is a potent anti-inflammatory cytokine, LPS-induced microglial activation in the aged brain is prolonged and is associated with development of depressive-like behavior. Our revised proposal addresses this critical problem in an innovative manner by identifying astrocytes as the pivotal cell in the failure to resolve microglial activation in the aged brain following immune challenge. Novel data provided here indicate that activated astrocytes in the aged brain have decreased IL-10 receptor-1 expression with corresponding reduced sensitivity to IL-10. This IL-10 insensitivity of aged astrocytes results in failure to produce TGF? and attenuate microglial activation. These findings fill a majo gap in the field about how microglia are regulated to prevent exaggerated neuroinflammation. Thus, the goal of this project is to test the hypothesis that prolonged neuroinflammation in the aged brain following a peripheral inflammatory challenge is caused by impaired astrocyte-dependent regulation of microglia. To address this hypothesis, three specific aims are proposed.
In Aim -1, we will determine the degree to which reduced IL-10 sensitivity of aged astrocytes impairs their ability to regulate active microglia in vivo and ex vivo. Age-related issues in the functionality of IL-10/IL-10R1 signaling in astrocytes following immune challenge will be delineated and corresponding deficits in TGF?/TGF?R signaling in microglia will be determined. We will use several unique approaches to determine microglia and astrocyte mRNA copy number, protein expression, morphology, and ex vivo interactions in adult and aged mice after immune challenge.
In Aim -2, we will ascertain the extent to which viral gene therapy enhancement of IL-10R1 specifically on astrocytes restores microglial regulation and prevents depressive-like behavior in aged mice following immune challenge.
In Aim -3, we will determine if restoration of TGF? in the aged brain circumvents IL-10 insensitivity of astrocytes after immune challenge and attenuates microglia hyper-activation and prevents depressive-like behavior. Understanding how impaired IL-10 re-programming of astrocytes contributes to neuroinflammation and depressive-like behavior will lead to new interventions that target astrocytes in order to reduce neuropsychiatric complications associated with inflammatory challenge in the aged.
In the elderly, peripheral infection is associated with a higher incidence of neuropsychiatric complications, but the mechanisms underlying these complications are unknown. We propose that these inflammatory-related deficits in behavior are caused by impaired regulation of microglial activation in the aged brain. The goal of this proposal is to understand how IL-10-mediated regulation of astrocytes is impaired in the aged brain, and how this problem leads to exaggerated microglial activation and the development of depressive-like behavior following immune challenge. In this application, we will use a murine model of aging to test the hypothesis that prolonged neuroinflammation and the development of depressive-like behavior in the aged following a peripheral inflammatory challenge is caused by impaired astrocyte-dependent regulation of microglia. Completion of these studies will lead to novel interventions to enhance astrocyte sensitivity to IL-10 and attenuate prolonged neurobehavioral complications associated with peripheral immune challenge in the aged.
