Nox4-dependent upregulation of S100A4 after peripheral nerve injury modulates neuropathic pain processing

Gesine Wack, Katharina Metzner, Miriam S. Kuth, Elena Wang, Anne Bresnick, Ralf P. Brandes, Katrin Schröder, Ilka Wittig, Achim Schmidtko, Wiebke Kallenborn-Gerhardt

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Previous studies suggested that reactive oxygen species (ROS) produced by NADPH oxidase 4 (Nox4) affect the processing of neuropathic pain. However, mechanisms underlying Nox4-dependent pain signaling are incompletely understood. In this study, we aimed to identify novel Nox4 downstream interactors in the nociceptive system. Mice lacking Nox4 specifically in sensory neurons were generated by crossing Advillin-Cre mice with Nox4fl/fl mice. Tissue-specific deletion of Nox4 in sensory neurons considerably reduced mechanical hypersensitivity and neuronal action potential firing after peripheral nerve injury. Using a proteomic approach, we detected various proteins that are regulated in a Nox4-dependent manner after injury, including the small calcium-binding protein S100A4. Immunofluorescence staining and Western blot experiments confirmed that S100A4 expression is massively up-regulated in peripheral nerves and dorsal root ganglia after injury. Furthermore, mice lacking S100A4 showed increased mechanical hypersensitivity after peripheral nerve injury and after delivery of a ROS donor. Our findings suggest that S100A4 expression is up-regulated after peripheral nerve injury in a Nox4-dependent manner and that deletion of S100A4 leads to an increased neuropathic pain hypersensitivity.

Original languageEnglish (US)
Pages (from-to)155-167
Number of pages13
JournalFree Radical Biology and Medicine
StatePublished - May 20 2021


  • Knockout mice
  • NADPH oxidase 4
  • Nerve injury
  • Neuropathic pain
  • Nox4
  • S100A4

ASJC Scopus subject areas

  • Biochemistry
  • Physiology (medical)


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