Spinal Microgliosis Due to Resident Microglial Proliferation Is Required for Pain Hypersensitivity After Peripheral Nerve Injury

Cell Rep. 2016 Jul 19;16(3):605-14. doi: 10.1016/j.celrep.2016.06.018. Epub 2016 Jun 30.

Abstract

Peripheral nerve injury causes neuropathic pain accompanied by remarkable microgliosis in the spinal cord dorsal horn. However, it is still debated whether infiltrated monocytes contribute to injury-induced expansion of the microglial population. Here, we found that spinal microgliosis predominantly results from local proliferation of resident microglia but not from infiltrating monocytes after spinal nerve transection (SNT) by using two genetic mouse models (CCR2(RFP/+):CX3CR1(GFP/+) and CX3CR1(creER/+):R26(tdTomato/+) mice) as well as specific staining of microglia and macrophages. Pharmacological inhibition of SNT-induced microglial proliferation correlated with attenuated neuropathic pain hypersensitivities. Microglial proliferation is partially controlled by purinergic and fractalkine signaling, as CX3CR1(-/-) and P2Y12(-/-) mice show reduced spinal microglial proliferation and neuropathic pain. These results suggest that local microglial proliferation is the sole source of spinal microgliosis, which represents a potential therapeutic target for neuropathic pain management.

MeSH terms

  • Animals
  • CX3C Chemokine Receptor 1 / metabolism
  • Cell Proliferation / physiology*
  • Chemokine CX3CL1 / metabolism
  • Disease Models, Animal
  • Macrophages / metabolism
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microglia / metabolism
  • Microglia / pathology*
  • Monocytes / metabolism
  • Monocytes / pathology
  • Neuralgia / metabolism
  • Neuralgia / pathology*
  • Pain Measurement / methods
  • Peripheral Nerve Injuries / metabolism
  • Peripheral Nerve Injuries / pathology*
  • Receptors, Purinergic P2Y12 / metabolism
  • Spinal Cord Dorsal Horn / metabolism
  • Spinal Cord Dorsal Horn / pathology*
  • Spinal Nerves / metabolism
  • Spinal Nerves / pathology

Substances

  • CX3C Chemokine Receptor 1
  • Chemokine CX3CL1
  • Cx3cr1 protein, mouse
  • P2ry12 protein, mouse
  • Receptors, Purinergic P2Y12