title: Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion.
abstract: Increasing evidence indicates that the pathogenesis of neuropathic pain is mediated through spinal cord microglia activation. The intracellular protease caspase-6 (CASP6) is known to regulate neuronal apoptosis and axonal degeneration; however, the contribution of microglia and CASP6 in modulating synaptic transmission and pain is unclear. Here, we found that CASP6 is expressed specifically in C-fiber axonal terminals in the superficial spinal cord dorsal horn. Animals exposed to intraplantar formalin or bradykinin injection exhibited CASP6 activation in the dorsal horn. Casp6-null mice had normal baseline pain, but impaired inflammatory pain responses. Furthermore, formalin-induced second-phase pain was suppressed by spinal injection of CASP6 inhibitor or CASP6-neutralizing antibody, as well as perisciatic nerve injection of CASP6 siRNA. Recombinant CASP6 (rCASP6) induced marked TNF-α release in microglial cultures, and most microglia within the spinal cord expressed Tnfa. Spinal injection of rCASP6 elicited TNF-α production and microglia-dependent pain hypersensitivity. Evaluation of excitatory postsynaptic currents (EPSCs) revealed that rCASP6 rapidly increased synaptic transmission in spinal cord slices via TNF-α release. Interestingly, the microglial inhibitor minocycline suppressed rCASP6 but not TNF-α-induced synaptic potentiation. Finally, rCASP6-activated microglial culture medium increased EPSCs in spinal cord slices via TNF-α. Together, these data suggest that CASP6 released from axonal terminals regulates microglial TNF-α secretion, synaptic plasticity, and inflammatory pain.
authors: Temugin
authors: T
authors: Berta
authors: Chul-Kyu
authors: CK
authors: Park
authors: Zhen-Zhong
authors: ZZ
authors: Xu
authors: Ruo-Gang
authors: RG
authors: Xie
authors: Tong
authors: T
authors: Liu
authors: Ning
authors: N
authors: Lü
authors: Yen-Chin
authors: YC
authors: Liu
authors: Ru-Rong
authors: RR
authors: Ji
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology; D001920:Bradykinin; D053178:Caspase 6 / Q000502:physiology*; D061945:Caspase Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D005557:Formaldehyde; D006930:Hyperalgesia / Q000139:chemically induced / Q000201:enzymology; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology; D017774:Long-Term Potentiation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000201:enzymology / Q000378:metabolism*; D009437:Neuralgia / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology; D009473:Neuronal Plasticity; D009475:Neurons, Afferent / Q000201:enzymology; D018408:Patch-Clamp Techniques; D059010:Single-Cell Analysis; D013116:Spinal Cord / Q000187:drug effects / Q000201:enzymology / Q000503:physiopathology; D013569:Synapses / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D061945:Caspase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D005557:Formaldehyde; C505516:Casp6 protein, mouse; D053178:Caspase 6; D001920:Bradykinin