Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system

Abstract

Recent studies suggest that activation of the peripheral immune system elicits a discordant central (i.e., in the brain) inflammatory response in aged but otherwise healthy subjects compared with younger cohorts. A fundamental difference in the reactive state of microglial cells in the aged brain has been suggested as the basis for this discordant inflammatory response. Thus, the aging process appears to serve as a "priming" stimulus for microglia, and upon secondary stimulation with a triggering stimulus (i.e., peripheral signals communicating infection), these primed microglia release excessive quantities of proinflammatory cytokines. Subsequently, this exaggerated cytokine release elicits exaggerated behavioral changes including anorexia, hypersomnia, lethargy, decreased social interaction, and deficits in cognitive and motor function (collectively known as the sickness behavior syndrome). Whereas this reorganization of host priorities is normally adaptive in young subjects, there is a propensity for this response to be maladaptive in aged subjects, resulting in greater severity and duration of the sickness behavior syndrome. Consequently, acute bouts of cognitive impairment in elderly subjects increase the likelihood of poor self-care behaviors (i.e., anorexia, weight loss, noncompliance), which ultimately leads to higher rates of hospitalization and mortality.

Fig. 1.

Parallel communication routes between the immune system and brain. The neural pathway involves rapid communication of immune signals via primary afferent nerves. For instance, peripherally produced cytokines directly stimulate vagal afferents from the liver to elicit central responses. In the diffusion pathway, blood-derived cytokines passively traverse the blood-brain barrier at “leaky” brain regions, including the circumventricular organs. Transportation of peripheral cytokines occurs by an energy-dependent, saturable process involving transporters integral in the blood-brain barrier. A fourth route of communication currently being investigated involves endothelial cells composing the blood-brain barrier. It is believed that circulating cytokines bind to endothelial receptors to elicit the release of immune molecules (e.g., cytokines, NOS, etc.) directly into brain regions. Regardless of the pathway, inflammatory mediators released into the CNS activate brain microglial cells to release inflammatory cytokines, which subsequently bind neuronal receptors in specific brain regions (e.g., hippocampus) to initiate the sickness behavior syndrome.

Fig. 2.

Microglial cells in the aged brain elicit a discordant inflammatory response upon activation by the peripheral innate immune system. (A) Similar to the priming paradigm proposed for peripheral macrophages, microglial cells in the aged brain may be primed as characterized by phenotypic alterations (e.g., increased expression of cell-surface markers). Upon receiving a triggering stimulus, these primed microglia release excessive concentrations of inflammatory cytokines in the CNS. (B) Evidence suggests the aged mouse brain responds to peripheral infection with a more exaggerated cytokine response compared with the adult mouse brain. Subsequent to peripheral immune stimulation with lipopolysaccharide (LPS), the release of IL-1β is higher in the aged vs. adult mouse brain [10]. (C) Both priming and triggering stimuli appear necessary to cause a discordant response by microglial cells in the aged brain. Cytokines released by microglia normally initiate an adaptive sickness behavior syndrome that includes anorexia, fever, and decreased social exploration. However, excessive cytokine release by primed and activated microglia elicits a discordant, maladaptive sickness behavior syndrome in the aged animal.