TY  - JOUR
A1  - Zschiebsch, Katja
A1  - Fischer, Caroline
A1  - Wilken-Schmitz, Annett
A1  - Geisslinger, Gerd
A1  - Channon, Keith
A1  - Watschinger, Katrin
A1  - Tegeder, Irmgard
T1  - Mast cell tetrahydrobiopterin contributes to itch in mice
T2  - Journal of cellular and molecular medicine
N2  - GTP cyclohydrolase (GCH1) governs de novo synthesis of the enzyme cofactor, tetrahydrobiopterin (BH4), which is essential for biogenic amine production, bioactive lipid metabolism and redox coupling of nitric oxide synthases. Overproduction of BH4 via upregulation of GCH1 in sensory neurons is associated with nociceptive hypersensitivity in rodents, and neuron‐specific GCH1 deletion normalizes nociception. The translational relevance is revealed by protective polymorphisms of GCH1 in humans, which are associated with a reduced chronic pain. Because myeloid cells constitute a major non‐neuronal source of BH4 that may contribute to BH4‐dependent phenotypes, we studied here the contribution of myeloid‐derived BH4 to pain and itch in lysozyme M Cre‐mediated GCH1 knockout (LysM‐GCH1−/−) and overexpressing mice (LysM‐GCH1‐HA). Unexpectedly, knockout or overexpression in myeloid cells had no effect on nociceptive behaviour, but LysM‐driven GCH1 knockout reduced, and its overexpression increased the scratching response in Compound 48/80 and hydroxychloroquine‐evoked itch models, which involve histamine and non‐histamine dependent signalling pathways. Mechanistically, GCH1 overexpression increased BH4, nitric oxide and hydrogen peroxide, and these changes were associated with increased release of histamine and serotonin and degranulation of mast cells. LysM‐driven GCH1 knockout had opposite effects, and pharmacologic inhibition of GCH1 provided even stronger itch suppression. Inversely, intradermal BH4 provoked scratching behaviour in vivo and BH4 evoked an influx of calcium in sensory neurons. Together, these loss‐ and gain‐of‐function experiments suggest that itch in mice is contributed by BH4 release plus BH4‐driven mediator release from myeloid immune cells, which leads to activation of itch‐responsive sensory neurons.
KW  - inflammation
KW  - nitric oxide
KW  - pain
KW  - pruritus
KW  - redox signalling
KW  - sensory neurons
KW  - tetrahydrobiopterin
Y1  - 2018
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/48431
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-484319
SN  - 1582-4934
SN  - 1582-1838
N1  - This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
VL  - 22
SP  - 1
EP  - 16
PB  - Wiley-Blackwell
CY  - Hoboken, NJ
ER  -