Spinal macrophages resolve nociceptive hypersensitivity after peripheral injury

Neuron. 2021 Apr 21;109(8):1274-1282.e6. doi: 10.1016/j.neuron.2021.02.018. Epub 2021 Mar 4.


Peripheral nerve injury induces long-term pro-inflammatory responses in spinal cord glial cells that facilitate neuropathic pain, but the identity of endogenous cells that resolve spinal inflammation has not been determined. Guided by single-cell RNA sequencing (scRNA-seq), we found that MRC1+ spinal cord macrophages proliferated and upregulated the anti-inflammatory mediator Cd163 in mice following superficial injury (SI; nerve intact), but this response was blunted in nerve-injured animals. Depleting spinal macrophages in SI animals promoted microgliosis and caused mechanical hypersensitivity to persist. Conversely, expressing Cd163 in spinal macrophages increased Interleukin 10 expression, attenuated micro- and astrogliosis, and enduringly alleviated mechanical and thermal hypersensitivity in nerve-injured animals. Our data indicate that MRC1+ spinal macrophages actively restrain glia to limit neuroinflammation and resolve mechanical pain following a superficial injury. Moreover, we show that spinal macrophages from nerve-injured animals mount a dampened anti-inflammatory response but can be therapeutically coaxed to promote long-lasting recovery of neuropathic pain.

Keywords: macrophages; neuroinflammation; neuropathic pain; single-cell RNA-seq; spinal cord.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Disease Models, Animal
  • Hyperalgesia / metabolism*
  • Inflammation / metabolism
  • Macrophages / physiology*
  • Mice
  • Neuralgia / metabolism*
  • Nociception / physiology
  • Pain Measurement
  • Peripheral Nerve Injuries / metabolism*
  • Spinal Cord / metabolism*