Dual effect of tacrolimus on mast cell-mediated allergy and inflammation
through MAS-related G protein-coupled receptor-X2
Abstract
Background: Topical tacrolimus has been widely used in the
treatment of inflammatory and immune dermatoses for its
immunosuppression effect. However, a transient irritation like itching,
burning induced by tacrolimus is common when initial application, which
is similar to pseudo-allergic reaction. MAS-related G protein-coupled
receptor-X2 (MRGPRX2) in mast cells (MCs) mediates drug-induced
pseudo-allergic reaction and IgE-independent pruritis in chronic skin
diseases. Whether MRGPRX2 participates in above tacrolimus adverse
reaction should be addressed. Further, immunosuppression mechanism of
tacrolimus on MCs is greatly ignored. Methods: Wild-type (WT)
mice, kit w-sh/w-sh mice and MrgprB2 deficient (MUT)
mice were applied to explore the mechanism of initial irritant reaction
and immunosuppression of tacrolimus on the skin MrgprB2 in MCs in
vivo. LAD2 cells and MRGPRX2-knockdown LAD2 cells were used to confirm
the regulation of MRGPRX2 by tacrolimus in vitro.
Results: Tacrolimus could trigger IgE-independent dermatitis
when initial application through MrgprB2-related MCs degranulation.
Using FK-DNS, a fluorescently labeled tacrolimus, we found tacrolimus
could bind to MRGPRX2 directly. Interestingly, after long-term
tacrolimus treatment, the initial itching and inflammatory reaction
faded away without IgE change. Hence, longstanding treatment with
tacrolimus suppressed MRGPRX2/B2 expression and decreased inflammatory
cytokines release. Conclusion: Our study provides for the first
time a novel target for tacrolimus, demonstrating that short-term
tacrolimus treatment induces pseudo-allergic reaction via MRGPRX2/B2 in
MCs, while long-term treatment dampens MRGPRX2/B2 expression, leading to
decreased inflammatory cytokines release and immune cells recruitment,
which may contribute to its potent immunosuppression effect in the
treatment of inflammatory and immune skin diseases.