Poised for action: USP18 restrains microglial activation in the white matter

Microglia are the resident macrophage population of the central nervous system (CNS) and are required for CNS development, homeostasis, and immune defense. Dysregulated microglial activity is involved in the pathogenesis of neuro-degenerative conditions and is the dominant driver of neuro-inflammatory diseases named "microgliopathies". In this issue of The EMBO Journal, Goldmann et al reveal that white matter microglia in mice are actively maintained in a quiescent state via the ubiquitin-specific protease (Usp) 18 (Goldmann et al, 2015). Removing this molecular blocker results in aggressive type I IFN-mediated pathology, with features reminiscent of human microgliopathy. This study furthers our knowledge of the roles and regulation of microglial populations, adds insight into the processes underlying neuro-inflammation, and broadens our consideration of immune regulation to include the concept of active restraint as a necessary component to avoid excessive inflammation.