Figure 1. Microglial priming during aging and stress.

In the healthy CNS, a steady-state inactive microglial phenotype is associated with limited pattern recognition receptor expression (and low extracellular damage-associated molecular pattern (DAMP) expression), activation of neuron-microglia signaling pathways, and typical daily rhythms in circadian and inflammatory genes. During aging or after stress, microglia develop a “primed” phenotype that does not increase effector function but sensitizes the cells to subsequent stimulation. Primed microglia upregulate pattern recognition receptors, have more DAMPs in the extracellular environment, and de-activated neuron-microglia signaling (dis-inhibition of microglial). When primed microglia experience an immune challenge, the cell responds with an exaggerated inflammatory response that can be prolonged and can exacerbate pathology. Processes shown here represent key common mechanisms driving microglia priming; please see text for more details.