Could an endoneurial endothelial crosstalk between Wnt/β-catenin and Sonic Hedgehog pathways underlie the early disruption of the infra-orbital blood-nerve barrier following chronic constriction injury?

Abstract : Background: Blood-nerve barrier (BNB) disruption is pivotal in the development of neuroinflammation, peripheral sensitization and neuropathic pain after peripheral nerve injury (PNI). Activation of Toll-Like Receptor 4 (TLR4) and inactivation of Sonic Hedgehog (SHH) signaling pathways within the endoneurial endothelial cells (EEC) are key events, resulting in the infiltration of harmful molecules and immunocytes within the nerve parenchyma. However, preemptive inactivation of TLR4 signaling or sustained activation of SHH signaling do not prevent the local alterations observed following PNI, suggesting the implication of another signaling pathway. Methods: Using a classical neuropathic pain model, the infra-orbital nerve chronic constriction injury (IoN-CCI), and a neuritis model, the simple nerve stretch (SNS), we investigated the role of the Wnt/β-catenin pathway, its interactions with the TLR4 and SHH pathways and the phenotypical transition between neuritis and neuropathy. In PNI models (CCI and SNS) vs controls, mRNA expression levels and/or immunochemical detection of major readouts (Frizzled-7, VE-cadherin, Patched-1, Gli-1) and/or Tight Junction (TJ) proteins (Claudin 1,5, Occludin) were assessed. Vascular permeability (VP) was assessed by sodium fluorescein extravasation. Results: IoN-CCI induced early alterations in the VE-cadherin/β-catenin/Frizzled-7 complex, shown to participate in local BNB disruption via a β-catenin-dependent TJ protein downregulation. Wnt pathway also mediated a crosstalk between TLR4 and SHH signaling within EEC. Finally, differences in both the involvement of Wnt/β-catenin signaling and endoneural VP were observed between SNS and CCI, respectively mild reversible VP (mediated by Wnt/β-catenin signaling) vs irreversible VP (mediated by active Wnt/β-catenin and inactive SHH signaling). Such differential involvement of Wnt/β-catenin and SHH pathways might explain the transition between neuritis and neuropathy. Conclusion: A crosstalk between Wnt/β-catenin- and SHH-mediated signaling pathways within EEC mediates the chronic disruption of the BNB following PNI, resulting in increased irreversible endoneurial VP. Post-traumatic peripheral neuropathic pain could thus be considered a disease of VP.
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Nathan Moreau, Annie Mauborgne, Ignacio Romero, Pierre-Olivier Couraud, Babette Weksler, et al.. Could an endoneurial endothelial crosstalk between Wnt/β-catenin and Sonic Hedgehog pathways underlie the early disruption of the infra-orbital blood-nerve barrier following chronic constriction injury?. Molecular Pain, BioMed Central, 2017, 13, ⟨10.1177/1744806917727625⟩. ⟨hal-01587933⟩

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