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 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.

A cross-sectional comparison of ethanol-related cytokine expression in the hippocampus of young and aged Fischer 344 rats

“…It is likely that while peak cytokine responses during intoxication could remain stable across age, the resolution of the inflammatory response could differ across ontogeny. Prior work has shown that the aged neuroimmune system can exhibit protracted neuroimmune activation following a peripheral immune challenge (Norden et al, 2016; Huang, Henry, Dantzer, Johnson, & Godbout, 2008). While a rapid resolution of RANGE is seen at 18 h in adult rats, examination of this time point in aged animals may yield alternative results that would help inform conclusions regarding alcohol effects on neuroimmune function in late aging.…”

“…For instance, blunted peripheral expression of anti-inflammatory cytokines such as IL-10 has been shown in the aged animal following immune challenge and spinal cord injury models as compared to young controls (Williams, José, Brown, & Chambers, 2015; Zhang, Bailey, Braun, & Gensel, 2015). In the brain, exaggerated levels of cytokines are associated with aging, yet insensitivity to the effects of anti-inflammatory cytokines such as IL-10 has been reported, indicating shifts in the regulation of neuroinflammation (Norden, Trojanowski, Walker, & Godbout, 2016). Consistent with this, aged mice have been shown to exhibit sensitized cytokine responses and a protracted recovery from immune challenge (Huang, Henry, Dantzer, Johnson, & Godbout, 2008).…”

Neonatal infection produces significant changes in immune function with no associated learning deficits in juvenile rats

“…Indeed, if we consider findings from aged rodents, this is not a surprising notion. Aged rodents are far more vulnerable to the consequences of immune activation compared with younger animals (Bilbo, ; Liu et al, ; Norden et al, ; for a review see Niraula et al, ) and, in humans cognitive impairments observed in the aged population following infection or illness are prolonged and more severe relative to a younger population (Bodles and Barger, ; Perry, ). Much like aging, it is likely that earlier periods of neural development (e.g.…”

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

“…Under homeostatic conditions, astrocytes respond to microgliainduced inflammatory stimulation by producing antiinflammatory cytokines such as IL-10 and TGF-β, which act as a feedback loop to decrease microglial activation (Norden et al, 2015b(Norden et al, , 2016. Aged astrocytes fail to restrain microglial activation probably due to a loss of or decreased surface expression IL-10 receptors in older compared with younger astrocytes (Norden et al, 2015b(Norden et al, , 2016.…”