IKK/NF-κB-dependent Satellite Glia Activation Induces Spinal Cord Microglia Activation and Neuropathic Pain via Ganglioside-TLR2 Signaling

Objectives: Increasing evidence supports that both microglia and satellite glial cell (SGC) activation play a causal role in neuropathic pain development after peripheral nerve injury, yet the activation mechanisms and their contribution to neuropathic pain remain elusive. The objective of our research is to elucidate the in vivo role of SGC activation in the nerve injury-induced neuropathic pain.
Methods: We have developed a conditional knockout mice in which NF-kB-dependent SGC activation is abrogated. In these mice, we induced neuropathic pain by L5 spinal nerve transection injury. Pain induction was monitored by von Frei test and Hargreaves test. Spinal cord microglia and SGC activation were assessed by immunohistochemistry and gene expression profile.
Results: The data show that IKK/NF-kB-dependent SGC activation after nerve injury leads to spinal cord microglia activation and pain hypersensitivity using SGC-specific Ikkb conditional knockout mice. As an underlying mechanism, we found that SGC activation induces St3gal2 expression in sensory neurons and subsequently leads to aberrant increase in ganglioside GT1b in afferent axons in the dorsal horn. In the spinal cord, GT1b functions as an endogenous agonist of toll-like receptor 2 (TLR2) to activate microglia and thereby induces pain central sensitization.


Conclusions: Taken together, we present a novel mechanism for spinal cord microglia activation in nerve injury-induced neuropathic pain that is dependent on SGC activation, GT1b increase in the dorsal horn, and activation of microglial TLR2.