The microglial cell response to sterile nerve injury in the brain is regulated by IRF8

Abstract

Abstract Microglia, the resident immune cells of the central nervous system (CNS), respond vigorously to insults such as nerve injury. We have shown previously in the normal CNS the properties of microglia are dramatically altered in the absence of IRF8. Here we examined whether IRF8 is involved in the microglial cell response to sterile nerve injury. Facial nerve axotomy (FNA) was performed in wild type (WT) and IRF8−/− (KO) mice and the brain removed at different days post-injury (dpi). In brains from IRF8 KO mice, nucleoside diphosphatase (NDPase) histochemistry revealed gross alterations in the morphology of microglia, which were stunted and hypertrophied but were present in comparable numbers with WT. In WT mice, a progressive increase in microglial cell activation was observed peaking at 7 dpi and was accompanied by dense staining for lectin, NDPase and CD11b. By contrast, in IRF8 KO mice, the microglial cell activation was grossly attenuated with the density of staining for lectin, NDPase and CD11b reduced significantly. The attenuated microglial cell activation in IRF8 KO mice was paralleled by a significant decrease in microglial cell proliferation at 7 and 14 dpi. The wrapping of individual motor neuron cell bodies in the axotomised facial nucleus by microglia involved in synaptic stripping and phagocytosis was incomplete in IRF8 KO mice and was accompanied by an increase in degenerated neurons. These findings show that in addition to maintenance of homeostatic properties, IRF8 also has an important role in regulating a number of key processes in the microglial cell response to neuronal injury.