Regulation of microglial activation in stroke in aged mice: a translational study

Numerous neurochemical changes occur with aging and stroke mainly affects the elderly. Our previous study has found interferon regulatory factor 5 (IRF5) and 4 (IRF4) regulate neuroinflammation in young stroke mice. However, whether the IRF5-IRF4 regulatory axis has the same effect in aged brains is not known. In this study, aged (18-20-month-old), microglial IRF5 or IRF4 conditional knockout (CKO) mice were subjected to a 60-min middle cerebral artery occlusion (MCAO). Stroke outcomes were quantified at 3d after MCAO. Flow cytometry and ELISA were performed to evaluate microglial activation and immune responses. We found aged microglia express higher levels of IRF5 and lower levels of IRF4 than young microglia after stroke. IRF5 CKO aged mice had improved stroke outcomes; whereas worse outcomes were seen in IRF4 CKO vs. their flox controls. IRF5 CKO aged microglia had significantly lower levels of IL-1β and CD68 than controls; whereas significantly higher levels of IL-1β and TNF-α were seen in IRF4 CKO vs. control microglia. Plasma levels of TNF-α and MIP-1α were decreased in IRF5 CKO vs. flox aged mice, and IL-1β/IL-6 levels were increased in IRF4 CKO vs. controls. The anti-inflammatory cytokines (IL-4/IL-10) levels were higher in IRF5 CKO, and lower in IRF4 CKO aged mice vs. their flox controls. IRF5 and IRF4 signaling drives microglial pro- and anti-inflammatory response respectively; microglial IRF5 is detrimental and IRF4 beneficial for aged mice in stroke. IRF5-IRF4 axis is a promising target for developing new, effective therapeutic strategies for the cerebral ischemia.