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.
Highlights
Katja Zschiebsch and Caroline Fischer authors Contributed .GTP cyclohydrolase 1 (GCH1) is the first‐step, rate‐limiting enzyme in the enzymatic cascade that leads to the generation of the enzyme cofactor, tetrahydrobiopterin (BH4)
Inhibition of GCH1 with diamino hydroxypyrimidine (DAHP) reliably reduces nociceptive hypersensitivity in rodent models of acute and chronic inflammatory and neuropathic pain,[9,24,35] and genetic polymorphisms contribute to chronic pain in humans.[9]
The present study assessed if and how BH4 from myeloid immune cells contributes to BH4‐dependent pain, inflammation and itch, either by changing enzyme functions and mediator release from these cells or by being released itself to act on neighbouring neurons
Summary
Katja Zschiebsch and Caroline Fischer authors Contributed . GTP cyclohydrolase 1 (GCH1) is the first‐step, rate‐limiting enzyme in the enzymatic cascade that leads to the generation of the enzyme cofactor, tetrahydrobiopterin (BH4). Activated immune cells, including human peripheral blood monocytes, release BH4 into the extracellular space upon stimulation,[9] and BH4 injection causes nociceptive hypersensitivity.[9,24] immune cell derived‐BH4 may contribute to pain and itch via two routes (a) indirectly, by regulating mediator production and release and (b) directly by being released itself to act on neighbouring sensory neurons. To address this hypothesis, we generated mice with myeloid cell specific knockout or overexpression of GCH1. We employed acute and inflammatory nociceptive models as well as Compound 48/80 (Cp48/80) and hydroxychloroquine‐evoked itch models to assess the functions of GCH1/BH4 in and from myeloid immune cells in the context of nociception and itch
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
