IRF8 Is a Critical Transcription Factor for Transforming Microglia into a Reactive Phenotype

SummaryMicroglia become activated by multiple types of damage in the nervous system and play essential roles in neuronal pathologies. However, how microglia transform into reactive phenotypes is poorly understood. Here, we identify the transcription factor interferon regulatory factor 8 (IRF8) as a critical regulator of reactive microglia. Within the spinal cord, IRF8 expression was normally low; however, the expression was markedly upregulated in microglia, but not in neurons or astrocytes, after peripheral nerve injury (PNI). IRF8 overexpression in cultured microglia promoted the transcription of genes associated with reactive states; conversely, IRF8 deficiency prevented these gene expressions in the spinal cord following PNI. Furthermore, IRF8-deficient mice were resistant to neuropathic pain, a common sequela of PNI, and transferring IRF8-overexpressing microglia spinally to normal mice produced pain. Therefore, IRF8 may activate a program of gene expression that transforms microglia into a reactive phenotype. Our findings provide a newly observed mechanism for microglial activation.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► Nerve injury induces interferon-regulatory factor 8 (IRF8) in microglia cells in the spinal cord ► IRF8 promotes expression of genes associated with reactive microglia ► Microglial IRF8 is necessary for one adverse effect of nerve injury, “neuropathic pain” ► This study provides a mechanism for microglial activation and neuronal disorders