Microglia exit the CNS in spinal root avulsion

Microglia are central nervous system (CNS)-resident cells. Their ability to migrate outside of the CNS, however, is not understood. Using time-lapse imaging in an obstetrical brachial plexus injury (OBPI) model, we show that microglia squeeze through the spinal boundary and emigrate to peripheral spinal roots. Although both macrophages and microglia respond, microglia are the debris-clearing cell. Once outside the CNS, microglia re-enter the spinal cord in an altered state. These peripheral nervous system (PNS)-experienced microglia can travel to distal CNS areas from the injury site, including the brain, with debris. This emigration is balanced by two mechanisms—induced emigration via N-methyl-D-aspartate receptor (NMDA) dependence and restriction via contact-dependent cellular repulsion with macrophages. These discoveries open the possibility that microglia can migrate outside of their textbook-defined regions in disease states.Microglia are normally assumed to be confined to the central nervous system (CNS), but this study shows show that after spinal root injury, microglia can exit the CNS to clear debris. Upon re-entry, the emigrated microglia are altered and can travel to distal areas such as the brain.Author summary: Cells are precisely organized in specific anatomical domains to ensure normal functioning of the nervous system. One such cell type, microglia, is usually considered to be confined to the central nervous system (CNS). Using time-lapse imaging to capture microglia as they migrate, we show that their characteristic CNS-residency can be altered after spinal root injury. After such injury, the microglia exit the spinal root to the periphery, where they clear debris at the injury site and then carry that debris back into the CNS. In addition, microglia that leave the CNS after spinal root injury become distinct from those that remain within the CNS. This emigration event of microglia after injury is driven by two mechanisms—dependence on glutamatergic signaling that induces their emigration to the injury and interactions with macrophages that prevent their ectopic exit from the spinal cord. Together, these discoveries raise the possibility that microglia could override their CNS-residency in certain disease contexts.