Mast cell tetrahydrobiopterin contributes to itch in mice

J Cell Mol Med. 2019 Feb;23(2):985-1000. doi: 10.1111/jcmm.13999. Epub 2018 Nov 18.


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.

Keywords: inflammation; nitric oxide; pain; pruritus; redox signalling; sensory neurons; tetrahydrobiopterin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biopterin / analogs & derivatives*
  • Biopterin / metabolism
  • Biopterin / pharmacology
  • Calcium / metabolism
  • Cell Degranulation / genetics
  • Chronic Pain / chemically induced
  • Chronic Pain / genetics
  • Chronic Pain / metabolism*
  • Female
  • GTP Cyclohydrolase / antagonists & inhibitors
  • GTP Cyclohydrolase / deficiency
  • GTP Cyclohydrolase / genetics*
  • GTP Cyclohydrolase / metabolism
  • Gene Expression
  • Histamine / metabolism
  • Humans
  • Hydroxychloroquine / administration & dosage
  • Integrases / genetics
  • Integrases / metabolism
  • Ion Transport
  • Male
  • Mast Cells / cytology
  • Mast Cells / drug effects
  • Mast Cells / metabolism*
  • Mice
  • Mice, Knockout
  • Muramidase / genetics
  • Muramidase / metabolism
  • Nitric Oxide / metabolism
  • Oxidation-Reduction
  • Pruritus / chemically induced
  • Pruritus / genetics
  • Pruritus / metabolism*
  • Sensory Receptor Cells / cytology
  • Sensory Receptor Cells / drug effects
  • Sensory Receptor Cells / metabolism
  • Serotonin / metabolism
  • Signal Transduction
  • Transgenes
  • p-Methoxy-N-methylphenethylamine / administration & dosage


  • Biopterin
  • Nitric Oxide
  • Serotonin
  • p-Methoxy-N-methylphenethylamine
  • Hydroxychloroquine
  • Histamine
  • Cre recombinase
  • Integrases
  • Muramidase
  • lysozyme M, mouse
  • GCH1 protein, human
  • GTP Cyclohydrolase
  • Gch1 protein, mouse
  • sapropterin
  • Calcium