Microglial pyroptosis drives neuropathic pain and targeting NLRP3 alleviates pain and neuroinflammation

Neuropathic pain is triggered by nerve damage or disease and involves chronic neuroinflammation driven by activated microglia releasing pro-inflammatory cytokines. PANoptosis, a complex cell death program encompassing apoptosis, pyroptosis, and necroptosis, has emerged as a key player in neuroinflammation. While individual PANoptosis pathway have been linked to pain, its systemic role in neuropathic pain remains unclear. This study explored the involvement of PANoptosis in microglia under neuropathic pain and its potential therapeutic targeting. After spinal nerve ligation (SNL), robust microglia activation and pro-inflammatory cytokines were increased in spinal dorsal horn. To figure out the major PANoptosis under neuropathic pain, bioinformatic analysis and protein analysis were explored by using spinal dorsal horn on 14 days of post injury. The results supported that pyroptosis was the dominant pathway after injury, and we further investigated pyroptosis-related markers on microglia specifically. Notably, pyroptosis marker (caspase-1) was elevated in microglia compared to apoptosis (cleaved caspase-3) and necroptosis (p-RIPK3) markers. This finding highlights microglia pyroptosis as a key driver of neuropathic pain development. To harness this knowledge therapeutically, we employed intrathecal injection of NLRP3 siRNA nanoparticles. NLRP3, a crucial component of the inflammasome complex triggering pyroptosis, served as our target. Strikingly, this intervention effectively alleviated mechanical allodynia, a hallmark of neuropathic pain, alongside reducing microgliosis and dampening microglial pyroptosis. Our findings reveal that microglia pyroptosis plays a key role in neuropathic pain and suggest NLRP3 siRNA nanoparticles as a promising therapeutic avenue for pain management.