Mast cell tetrahydrobiopterin contributes to itch in mice

Abstract

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.

Mast cell-derived BH4 is a critical mediator of postoperative pain

“…Although mast cell BH4 has been shown to regulate histamine release and itch responses in mice (Zschiebsch et al, 2019), we did not observe any effect of BH4 on histamine levels or its release upon degranulation. One reason for this discrepancy could be that the cre line, used in the itch study (LysMcre) to decipher mast cell-specific contributions, appears to be inactive in mast cells (Abram et al, 2014).…”

Sex- and cell-dependent contribution of peripheral high mobility group box 1 and TLR4 in arthritis-induced pain

“…However, we cannot rule out the involvement of other cells because minocycline, in addition to inhibiting macrophage activity, also has effects on T cells and neurons, 31 and the LysM promoter used for TLR4 deletion, besides being expressed in macrophages, is present also in other cells of the myeloid lineage. 57 …”