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

Abstract

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.

Figure 1. Usp18 controls microglial quiescence in the mouse brain white matter through regulation of IFNAR tonic and constitutive signaling

In the steady state, white matter microglial activation is regulated by the non-enzymatic function of Usp18 which competes with JAK1 for binding to the IFNAR2, hence preventing permanent detrimental activation triggered by constitutive low-level type I IFN stimulation that leads to the expression of ISG through ISRE. IFN: Interferon, IFNAR: IFN-α/β receptor, IRF: IFN regulatory factor, ISG: IFN-stimulated gene, ISRE: IFN-stimulated response elements, JAK: janus-activated kinase, 2′5′ OAS: 2′–5′ oligoadenylate synthetase, P: phosphorylation, STAT: signal transducers and activators of transcription, TYK: tyrosine kinase, Usp: ubiquitin-specific protease.