Editors' ChoiceNeuroscience

CSF-1 delivers a painful signal

Sci. Signal.  12 Jan 2016:
Vol. 9, Issue 410, pp. ec6
DOI: 10.1126/scisignal.aaf2141

Neuropathic pain is characterized by chronic hypersensitivity to pain stimuli. Microglial cells in the dorsal horn of the spinal cord become activated and proliferate after nerve injury. Microglial expression of several genes, including Itgam, Cx3cr1, Bdnf, and Ctss, is associated with pain, and microglia depend on signaling through the colony-stimulating factor 1 receptor (CSF-1R) for survival. Guan et al. investigated how injured dorsal root ganglion (DRG) neurons transmit the pain stimuli and activate microglia in the spinal cord. RNA-seq analysis performed on DRGs and the dorsal quadrant of spinal cords after nerve injury showed increased expression of Csf1, a gene that encodes colony-stimulating factor 1 (CSF-1), in DRG of the injured side and increased expression of Csf1r in the spinal cord. Immunostaining confirmed the presence of CSF-1 along with ATF3, a protein that increases in damaged peripheral neurons, in DRG neurons on the injured side. DRG neurons that were ligated (tied) after nerve injury accumulated CSF-1 at the site of ligation, suggesting that CSF-1was transported along the injured axon and is transported to the spinal cord. Hypersensitivity to pain was reduced in mice with Csf1 deletion, and CSF-1 injected into the spinal canal restored pain hypersensitivity. Nerve injury and spinal injection of CSF-1 resulted in increased expression of Itgam, Cx3cr1, Bdnf, and Ctss (genes induced in microglia in response to injury) without an induction of genes associated with monocytes in spinal cord. Nerve injury also stimulated the expression of Tyrobp, a gene that encodes an immune membrane adaptor protein, DAP12. BrdU labeling to identify proliferating cells combined with immunofluorescence analysis to identify the CSF-1R–positive cells showed that these cells proliferated after nerve injury or spinal injection of CSF1, which indicated proliferation of microglia. Although microglial proliferation occurred in Tyrobp–/– mice after injury or spinal injection of CSF1, these mice did not develop pain hypersensitivity or increased expression of Itgam, Cx3cr1, Bdnf, and Ctss after nerve injury or spinal injection of CSF-1, suggesting DAP12 was not necessary for microglial proliferation but was necessary for activation of the microglial cells and their participation in the hypersensitivity response. This study showed that the pain-producing functions of microglia are induced independently of microglial proliferation, indicating that intervention to block the pain functions may be possible without interfering with the repair and damage clearance functions of these cells.

Z. Guan, J. A. Kuhn, X. Wang, B. Colquitt, C. Solorzano, S. Vaman, A. K. Guan, Z. Evans-Reinsch, J. Braz, M. Devor, S. L. Abboud-Werner, L. L. Lanier, S. Lomvardas, A. I. Basbaum, Injured sensory neuron–derived CSF1 induces microglial proliferation and DAP12-dependent pain. Nat. Neurosci. 19, 94–101 (2016). [PubMed]