Mast cell tetrahydrobiopterin contributes to itch in mice

Abstract GTP cyclohydrolase ( GCH 1) governs de novo synthesis of the enzyme cofactor, tetrahydrobiopterin ( BH 4), which is essential for biogenic amine production, bioactive lipid metabolism and redox coupling of nitric oxide synthases. Overproduction of BH 4 via upregulation of GCH 1 in sensory neurons is associated with nociceptive hypersensitivity in rodents, and neuron‐specific GCH 1 deletion normalizes nociception. The translational relevance is revealed by protective polymorphisms of GCH 1 in humans, which are associated with a reduced chronic pain. Because myeloid cells constitute a major non‐neuronal source of BH 4 that may contribute to BH 4‐dependent phenotypes, we studied here the contribution of myeloid‐derived BH 4 to pain and itch in lysozyme M Cre‐mediated GCH 1 knockout (LysM‐ GCH 1 −/− ) and overexpressing mice (LysM‐ GCH 1‐ HA ). Unexpectedly, knockout or overexpression in myeloid cells had no effect on nociceptive behaviour, but LysM‐driven GCH 1 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, GCH 1 overexpression increased BH 4, nitric oxide and hydrogen peroxide, and these changes were associated with increased release of histamine and serotonin and degranulation of mast cells. LysM‐driven GCH 1 knockout had opposite effects, and pharmacologic inhibition of GCH 1 provided even stronger itch suppression. Inversely, intradermal BH 4 provoked scratching behaviour in vivo and BH 4 evoked an influx of calcium in sensory neurons. Together, these loss‐ and gain‐of‐function experiments suggest that itch in mice is contributed by BH 4 release plus BH 4‐driven mediator release from myeloid immune cells, which leads to activation of itch‐responsive sensory neurons.