Single-cell analysis of dorsal root ganglia reveals metalloproteinase signaling in satellite glial cells and pain

•Single-cell RNA sequencing reveals the diversity of satellite glial cells.•TIMP3 and metalloproteinase signaling are enriched in satellite glial cells.•TIMP3 expression modulates the response to mechanical and thermal stimuli, as well as the development of paclitaxel-induced neuropathic pain.•Metalloproteinase signaling in cultured satellite glial cells incubated with paclitaxel may serve as a platform for therapeutic discovery. Satellite glial cells (SGCs) are among the most abundant non-neuronal cells in dorsal root ganglia (DRGs) and closely envelop sensory neurons that detect painful stimuli. However, little is still known about their homeostatic activities and their contribution to pain. Using single-cell RNA sequencing (scRNA-seq), we were able to obtain a unique transcriptional profile for SGCs. We found enriched expression of the tissue inhibitor metalloproteinase 3 (TIMP3) and other metalloproteinases in SGCs. Small interfering RNA and neutralizing antibody experiments revealed that TIMP3 modulates somatosensory stimuli. TIMP3 expression decreased after paclitaxel treatment, and its rescue by delivery of a recombinant TIMP3 protein reversed and prevented paclitaxel-induced pain. We also established that paclitaxel directly impacts metalloproteinase signaling in cultured SGCs, which may be used to identify potential new treatments for pain. Therefore, our results reveal a metalloproteinase signaling pathway in SGCs for proper processing of somatosensory stimuli and potential discovery of novel pain treatments.