RIPK3 regulates microglial polarization through the TLR4/MyD88 pathway in neuropathic pain.

Abstract

Peripheral nerve injury activates microglia in the spinal, promoting microglial polarization and facilitating neuropathic pain progression. Necroptosis, a form of cell death, plays a crucial role in various neurological diseases and receptor-interacting protein kinases 3(RIPK3) a key molecular in the process. This study investigates to explore that RIPK3 regulates microglial polarization through the TLR4/MyD88 signaling pathway in neuropathic pain. By using a chronic constriction injury (CCI) model in mice, we found that peripheral nerve injury promoted M1 polarization and activated the TLR4/MyD88 pathway in spinal cord; in BV-2 microglia models, TNF-α/Z-VAD co-induction triggered M1 polarization through TLR4/MyD88 pathway, TLR4 antagonists suppressed these effects both in vivo and in vitro. Administration of GSK'872 (RIPK3 inhibitor) inhibited TLR4/MyD88 pathway, reduced microglial M1 polarization, promoted microglial M2 polarization and alleviated CCI-induced hyperalgesia. These findings suggest that necroptosis is a key cellular mechanism in peripheral injury-induced neuropathic pain and that RIPK3 regulates microglial polarization via the TLR4/MyD88 pathway, providing a new target for neuropathic pain treatment and clinical prevention.