Poster abstracts

Poster number 53 submitted by Shane ONeil

Microglia are Extrinsically Primed by the Aged Microenvironment

Shane M. ONeil (Neuroscience Graduate Program), Kristina G. Witcher (Neuroscience Graduate Program), Jonathan P. Godbout (Department of Neuroscience, Institute for Behavioral Medicine Research)

Abstract:
Microglia, the resident innate immune cells of the CNS, are responsible for propagating inflammatory signals from the periphery to the brain, where they drive the behavioral sickness response. With normal aging, these cells develop a pro-inflammatory, “primed” profile with increased expression of inflammatory mediators. Moreover, secondary immune challenge causes an exaggerated and prolonged neuroinflammatory response mediated by primed microglia in the aged brain. A critical question is if this age-associated profile can be reversed. Recent studies show CSF1R antagonism results in profound elimination of microglia in the adult. Therefore, we hypothesized CSF1R antagonist-mediated depletion of microglia in the aged brain would result in repopulation of new, unprimed microglia. Here we provide novel evidence that microglia in the brain of adult and aged mice were robustly eliminated following 3-week oral administration of CSF1R antagonist PLX5622. When the CSF1R antagonism was stopped, microglia repopulated the adult and aged brain at the same rate and efficiency with new cells no longer burdened with lipofuscin, the hallmark lipid debris of aging. In addition, repopulation reversed the age-associated increase in CD68 expression. FAC-sorting and RNA-Seq analysis of microglia revealed these new microglia took on the same primed mRNA profile as the cells they replaced. Moreover, RNA-Seq analysis of the brain provided evidence of reactive astrogliosis in aged mice independent of microglial depletion/repopulation. Lastly, peripheral innate immune challenge still caused an exaggerated microglial inflammatory response in the aged brain with prolonged behavioral deficits. These data indicate the local microenvironment of the aged brain significantly influences the profile of repopulating microglia. Taken together, aged microglia can proliferate and repopulate the CNS, but the resulting “new” microglia still adopt a pro-inflammatory profile characteristic of aging.

Keywords: microglia, aging, repopulation