Numerous inflammatory skin disorders display a high prevalence of itch. The Mas-related
G protein coupled receptor X2 (MRGPRX2) has been shown to modulate itch by inducing non-
IgE-mediated mast cell degranulation and the release of endogenous inducers of
pruritus. Various substances collectively known as basic
secretagogues, which include inflammatory
peptides and certain drugs, can trigger MRGPRX2 and thereby induce pseudo-
allergic reactions characterized by
histamine and
protease release as well as
inflammation. Here, we investigated the capacity of an immunomodulatory single-stranded
oligonucleotide (ssON) to modulate
IgE-independent mast cell degranulation and, more specifically, its ability to inhibit the basic
secretagogues compound 48/80 (C48/80)-and LL-37 in vitro and in vivo. We examined the effect of ssON on MRGPRX2 activation in vitro by measuring degranulation in a human mast cell line (
LAD2) and
calcium influx in MRGPRX2-transfected HEK293 cells. To determine the effect of ssON on itch, we performed behavioral studies in established mouse models and collected skin biopsies for histological analysis. Additionally, with the use of a
rosacea mouse model and RT-qPCR, we investigated the effect on ssON on LL-37-induced
inflammation. We reveal that both mast cell degranulation and
calcium influx in MRGPRX2 transfected HEK293 cells, induced by the
antimicrobial peptide LL-37 and the basic
secretagogue C48/80, are effectively inhibited by ssON in a dose-dependent manner. Further, ssON demonstrates a capability to inhibit LL-37 and C48/80 activation in vivo in two mouse models. We show that
intradermal injection of ssON in mice is able to block itch induced via C48/80 in a dose-dependent manner. Histological staining revealed that ssON inhibits acute mast cell degranulation in murine skin treated with C48/80. Lastly, we show that ssON treatment ameliorates LL-37-induced
inflammation in a
rosacea mouse model. Since there is a need for new
therapeutics targeting non-
IgE-mediated activation of mast cells, ssON could be used as a prospective
drug candidate to resolve itch and
inflammation in certain
dermatoses.