Injured sensory neuron-derived CSF1 induces microglia proliferation and DAP12-dependent pain

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