Injured Sensory Neuron-Derived CSF1 Induces Microglial Proliferation and DAP12-dependent Pain

Nat Neurosci. 2016 Jan;19(1):94-101. doi: 10.1038/nn.4189. Epub 2015 Dec 7.

Abstract

Although microglia have been implicated in nerve injury-induced neuropathic pain, the manner by which injured sensory neurons engage microglia remains unclear. We found that peripheral nerve injury induced de novo expression of colony-stimulating factor 1 (CSF1) in injured sensory neurons. CSF1 was transported to the spinal cord, where it targeted the microglial CSF1 receptor (CSF1R). Cre-mediated sensory neuron deletion of Csf1 completely prevented nerve injury-induced mechanical hypersensitivity and reduced microglial activation and proliferation. In contrast, intrathecal injection of CSF1 induced mechanical hypersensitivity and microglial proliferation. Nerve injury also upregulated CSF1 in motoneurons, where it was required for ventral horn microglial activation and proliferation. Downstream of CSF1R, we found that the microglial membrane adaptor protein DAP12 was required for both nerve injury- and intrathecal CSF1-induced upregulation of pain-related microglial genes and the ensuing pain, but not for microglial proliferation. Thus, both CSF1 and DAP12 are potential targets for the pharmacotherapy of neuropathic pain.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Proliferation*
  • Gene Expression Regulation*
  • Macrophage Colony-Stimulating Factor / metabolism*
  • Male
  • Mice
  • Microglia / metabolism*
  • Motor Neurons / metabolism*
  • Neuralgia / metabolism*
  • Peripheral Nerve Injuries / metabolism*
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / metabolism*
  • Sensory Receptor Cells / metabolism*
  • Up-Regulation

Substances

  • Adaptor Proteins, Signal Transducing
  • Csf1r protein, mouse
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Tyrobp protein, mouse
  • Macrophage Colony-Stimulating Factor