Central IRF4/5 Signaling Are Critical for Microglial Activation and Impact on Stroke Outcomes

Microglia and monocytes play a critical role in immune responses to cerebral ischemia. Previous studies have demonstrated that interferon regulatory factor 4 (IRF4) and IRF5 direct microglial polarization after stroke and impact outcomes. However, IRF4/5 are expressed by both microglia and monocytes, and it is not clear if it is the microglial (central) or monocytic (peripheral) IRF4-IRF5 regulatory axis that functions in stroke. In this work, young (8–12 weeks) male pep boy (PB), IRF4 or IRF5 flox, and IRF4 or IRF5 conditional knockout (CKO) mice were used to generate 8 types of bone marrow chimeras, to differentiate the role of central (PB-to-IRF CKO) vs. peripheral (IRF CKO-to-PB) phagocytic IRF4-IRF5 axis in stroke. Chimeras generated from PB and flox mice were used as controls. All chimeras were subjected to 60-min middle cerebral artery occlusion (MCAO) model. Three days after the stroke, outcomes and inflammatory responses were analyzed. We found that PB-to-IRF4 CKO chimeras had more robust microglial pro-inflammatory responses than IRF4 CKO-to-PB chimeras, while ameliorated microglial response was seen in PB-to-IRF5 CKO vs. IRF5 CKO-to-PB chimeras. PB-to-IRF4 or IRF5 CKO chimeras had worse or better stroke outcomes respectively than their controls, whereas IRF4 or 5 CKO-to-PB chimeras had similar outcomes compared to controls. We conclude that the central IRF4/5 signaling is responsible for microglial activation and mediates stroke outcomes.