Hydrogen peroxide production by epidermal dual oxidase 1 regulates nociceptive sensory signals
Anna Pató,
Kata Bölcskei,
Ágnes Donkó,
Diána Kaszás,
Melinda Boros,
Lilla Bodrogi,
György Várady,
Veronika F.S. Pape,
Benoit T. Roux,
Balázs Enyedi,
Zsuzsanna Helyes,
Fiona M. Watt,
Gábor Sirokmány,
Miklós Geiszt
Affiliations
Anna Pató
Department of Physiology, Semmelweis University, Faculty of Medicine, H-1094, Budapest, Hungary
Kata Bölcskei
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624, Pécs, Hungary
Ágnes Donkó
Department of Physiology, Semmelweis University, Faculty of Medicine, H-1094, Budapest, Hungary
Diána Kaszás
Department of Physiology, Semmelweis University, Faculty of Medicine, H-1094, Budapest, Hungary; MTA-SE Lendület Tissue Damage Research Group, Hungarian Academy of Sciences and Semmelweis University, H-1094, Budapest, Hungary; HCEMM-SE Inflammatory Signaling Research Group, Department of Physiology, Semmelweis University, H-1094, Budapest, Hungary
Melinda Boros
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624, Pécs, Hungary
Lilla Bodrogi
Department of Animal Biotechnology, Institute of Genetics and Biotechnology, Hungarian University of Agriculture and Life Sciences, H-2100, Gödöllő, Hungary
György Várady
Research Centre for Natural Sciences, Institute of Enzymology, H-1117, Budapest, Hungary
Veronika F.S. Pape
Department of Physiology, Semmelweis University, Faculty of Medicine, H-1094, Budapest, Hungary
Benoit T. Roux
Department of Physiology, Semmelweis University, Faculty of Medicine, H-1094, Budapest, Hungary; MTA-SE Lendület Tissue Damage Research Group, Hungarian Academy of Sciences and Semmelweis University, H-1094, Budapest, Hungary; HCEMM-SE Inflammatory Signaling Research Group, Department of Physiology, Semmelweis University, H-1094, Budapest, Hungary
Balázs Enyedi
Department of Physiology, Semmelweis University, Faculty of Medicine, H-1094, Budapest, Hungary; MTA-SE Lendület Tissue Damage Research Group, Hungarian Academy of Sciences and Semmelweis University, H-1094, Budapest, Hungary; HCEMM-SE Inflammatory Signaling Research Group, Department of Physiology, Semmelweis University, H-1094, Budapest, Hungary
Zsuzsanna Helyes
Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, H-7624, Pécs, Hungary; Eötvös Lorand Research Network, Chronic Pain Research Group, University of Pécs, H-7624, Pécs, Hungary; National Laboratory for Drug Research and Development, Magyar tudósok krt. 2, H-1117, Budapest, Hungary
Fiona M. Watt
European Molecular Biology Laboratory, 69117, Heidelberg, Germany
Gábor Sirokmány
Department of Physiology, Semmelweis University, Faculty of Medicine, H-1094, Budapest, Hungary; Corresponding author.
Miklós Geiszt
Department of Physiology, Semmelweis University, Faculty of Medicine, H-1094, Budapest, Hungary; Corresponding author.
Keratinocytes of the mammalian skin provide not only mechanical protection for the tissues, but also transmit mechanical, chemical, and thermal stimuli from the external environment to the sensory nerve terminals. Sensory nerve fibers penetrate the epidermal basement membrane and function in the tight intercellular space among keratinocytes. Here we show that epidermal keratinocytes produce hydrogen peroxide upon the activation of the NADPH oxidase dual oxidase 1 (DUOX1). This enzyme can be activated by increasing cytosolic calcium levels. Using DUOX1 knockout animals as a model system we found an increased sensitivity towards certain noxious stimuli in DUOX1-deficient animals, which is not due to structural changes in the skin as evidenced by detailed immunohistochemical and electron-microscopic analysis of epidermal tissue. We show that DUOX1 is expressed in keratinocytes but not in the neural sensory pathway. The release of hydrogen peroxide by activated DUOX1 alters both the activity of neuronal TRPA1 and redox-sensitive potassium channels expressed in dorsal root ganglia primary sensory neurons. We describe hydrogen peroxide, produced by DUOX1 as a paracrine mediator of nociceptive signal transmission.Our results indicate that a novel, hitherto unknown redox mechanism modulates noxious sensory signals.
