CSF1 is induced in injured (ATF3-positive) sensory neurons within 1 d of injury and is transported to the spinal cord, where it interacts with microglial CSF1R. Stimulated microglia, in turn, undergo a DAP12-independent proliferation/self-renewal and a DAP12-dependent neuropathic pain–associated gene induction, including BDNF and cathepsin S (CatS). The microglial–derived BDNF contributes to reduced GABAergic inhibitory control and a consequent hyperexcitability of dorsal horn pain transmission neurons. By cleaving CX3CL1 (fractalkine) from neuronal cell membranes, cathepsin S amplifies the activation of microglia. Whether the neuropathic pain phenotype is exacerbated by the concurrent CSF1-induced microglia self-renewal/proliferation and whether DAP12 contributes to that process remains to be determined.