IKK/NF-κB-dependent satellite glia activation induces spinal cord microglia activation and neuropathic pain after nerve injury

Pain. 2017 Sep;158(9):1666-1677. doi: 10.1097/j.pain.0000000000000959.


Increasing evidence indicates that both microglia and satellite glial cell (SGC) activation play causal roles in neuropathic pain development after peripheral nerve injury; however, the activation mechanisms and their contribution to neuropathic pain remain elusive. To address this issue, we generated Ikkβ conditional knockout mice (Cnp-Cre/Ikkβ; cIkkβ) in which IKK/NF-κB-dependent proinflammatory SGC activation was abrogated. In these mice, nerve injury-induced spinal cord microglia activation and pain hypersensitivity were significantly attenuated compared to those in control mice. In addition, nerve injury-induced proinflammatory gene expression and macrophage infiltration into the dorsal root ganglion (DRG) were severely compromised. However, macrophages recruited into the DRG had minimal effects on spinal cord microglia activation, suggesting a causal effect for SGC activation on spinal cord microglia activation. In an effort to elucidate the molecular mechanisms, we measured Csf1 expression in the DRG, which is implicated in spinal cord microglia activation after nerve injury. In cIkkβ mice, nerve injury-induced Csf1 upregulation was ameliorated indicating that IKK/NF-κΒ-dependent SGC activation induced Csf1 expression in sensory neurons. Taken together, our data suggest that nerve injury-induced SGC activation triggers Csf1 induction in sensory neurons, spinal cord microglia activation, and subsequent central pain sensitization.

MeSH terms

  • 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / genetics
  • 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase / metabolism
  • Animals
  • Cells, Cultured
  • Disease Models, Animal
  • Exploratory Behavior
  • Ganglia, Spinal / cytology
  • Gene Expression Regulation / genetics*
  • Hyperalgesia / physiopathology
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Macrophages / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • NF-kappa B / metabolism*
  • Nerve Tissue Proteins / metabolism
  • Neuralgia / etiology
  • Neuralgia / pathology*
  • Neuroglia / metabolism*
  • Neuroglia / pathology
  • Pain Threshold / physiology
  • Peripheral Nerve Injuries / complications
  • Satellite Cells, Perineuronal / metabolism
  • Spinal Cord / pathology*


  • NF-kappa B
  • Nerve Tissue Proteins
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase
  • Cnp protein, mouse