Targeting resident astrocytes attenuates neuropathic pain after spinal cord injury

Abstract Astrocytes derive from different lineages and play a critical role in neuropathic pain after spinal cord injury (SCI). Whether selective eliminating these main origins of astrocytes in lumbar enlargement could attenuate SCI-induced neuropathic pain remains unclear. In this study, astrocytes in lumbar enlargement were lineage traced, targeted and selectively eliminated through transgenic mice injected with an adeno-associated virus vector and diphtheria toxin. Pain-related behaviors were measured with an electronic von Frey apparatus and a cold/hot plate after SCI. RNA sequencing, bioinformatics analysis, molecular experiment and immunohistochemistry were used to explore the potential mechanisms after astrocyte elimination. Through lineage tracing, we concluded the resident astrocytes but not ependymal cells were the main origins of astrocytes-induced neuropathic pain. SCI induced mice to obtain significant pain symptoms and astrocyte activation in lumbar enlargement. Selective resident astrocytes elimination in lumbar enlargement could attenuate neuropathic pain and activate microglia. Interestingly, the type I interferons (IFNs) signal was significantly activated after astrocytes elimination, and the most activated Gene Ontology terms and pathways were associated with the type I IFNs signal which was mainly activated in microglia and further verified in vitro and in vivo. Furthermore, different concentrations of interferon and Stimulator of interferon genes (STING) agonist could activate the type I IFNs signal in microglia. Our results elucidate that selectively eliminating resident astrocytes attenuated neuropathic pain associated with type I IFNs signal activation in microglia. Targeting type I IFNs signal is proven to be an effective strategy for neuropathic pain treatment after SCI.