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Overproduction of\n BH<\/jats:styled-content>\n 4 via upregulation of\n GCH<\/jats:styled-content>\n 1 in sensory neurons is associated with nociceptive hypersensitivity in rodents, and neuron\u2010specific\n GCH<\/jats:styled-content>\n 1 deletion normalizes nociception. The translational relevance is revealed by protective polymorphisms of\n GCH<\/jats:styled-content>\n 1 in humans, which are associated with a reduced chronic pain. Because myeloid cells constitute a major non\u2010neuronal source of\n BH<\/jats:styled-content>\n 4 that may contribute to\n BH<\/jats:styled-content>\n 4\u2010dependent phenotypes, we studied here the contribution of myeloid\u2010derived\n BH<\/jats:styled-content>\n 4 to pain and itch in lysozyme M Cre\u2010mediated\n GCH<\/jats:styled-content>\n 1 knockout (LysM\u2010\n GCH<\/jats:styled-content>\n 1\n \u2212\/\u2212<\/jats:sup>\n ) and overexpressing mice (LysM\u2010\n GCH<\/jats:styled-content>\n 1\u2010\n HA<\/jats:styled-content>\n ). Unexpectedly, knockout or overexpression in myeloid cells had no effect on nociceptive behaviour, but LysM\u2010driven\n GCH<\/jats:styled-content>\n 1 knockout reduced, and its overexpression increased the scratching response in Compound 48\/80 and hydroxychloroquine\u2010evoked itch models, which involve histamine and non\u2010histamine dependent signalling pathways. Mechanistically,\n GCH<\/jats:styled-content>\n 1 overexpression increased\n BH<\/jats:styled-content>\n 4, nitric oxide and hydrogen peroxide, and these changes were associated with increased release of histamine and serotonin and degranulation of mast cells. LysM\u2010driven\n GCH<\/jats:styled-content>\n 1 knockout had opposite effects, and pharmacologic inhibition of\n GCH<\/jats:styled-content>\n 1 provided even stronger itch suppression. Inversely, intradermal\n BH<\/jats:styled-content>\n 4 provoked scratching behaviour in\u00a0vivo and\n BH<\/jats:styled-content>\n 4 evoked an influx of calcium in sensory neurons. Together, these loss\u2010 and gain\u2010of\u2010function experiments suggest that itch in mice is contributed by\n BH<\/jats:styled-content>\n 4 release plus\n BH<\/jats:styled-content>\n 4\u2010driven mediator release from myeloid immune cells, which leads to activation of itch\u2010responsive sensory neurons.\n <\/jats:p>","DOI":"10.1111\/jcmm.13999","type":"journal-article","created":{"date-parts":[[2018,11,19]],"date-time":"2018-11-19T02:50:15Z","timestamp":1542595815000},"page":"985-1000","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Mast cell tetrahydrobiopterin contributes to itch in mice"],"prefix":"10.1111","volume":"23","author":[{"given":"Katja","family":"Zschiebsch","sequence":"first","affiliation":[{"name":"Institute of Clinical Pharmacology Goethe\u2010University Hospital Frankfurt 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