Repopulated spinal cord microglia exhibit a unique transcriptome and contribute to pain resolution

Microglia are implicated as primarily detrimental in pain models; however, they exist across a continuum of states that contribute to homeostasis or pathology depending on timing and context. To clarify the specific contribution of microglia to pain progression, we take advantage of a temporally controlled transgenic approach to transiently deplete microglia. Unexpectedly, we observe complete resolution of pain coinciding with microglial repopulation rather than depletion. We find that repopulated mouse spinal cord microglia are morphologically distinct from control microglia and exhibit a unique transcriptome. Repopulated microglia from males and females express overlapping networks of genes related to phagocytosis and response to stress. We intersect the identified mouse genes with a single-nuclei microglial dataset from human spinal cord to identify human-relevant genes that may ultimately promote pain resolution after injury. This work presents a comprehensive approach to gene discovery in pain and provides datasets for the development of future microglial-targeted therapeutics. [Display omitted] •Selective depletion and repopulation of microglia completely reverse pain-like sensitivity•Reversal in pain trajectory coincides with microglial repopulation, not depletion•Repopulated microglia transcriptomes show active environmental surveillance after injury•Microglial genes are validated by intersection with human lumbar spinal cord microglial genes Donovan et al. demonstrate that depletion and repopulation, but not depletion alone, of CNS microglia contribute to complete pain resolution after peripheral injury. Key mouse microglial genes from these pro-resolution microglia are cross-referenced with a human spinal dorsal horn microglia dataset to reveal targets with high translational potential.