Abstract (246)
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, kitw-sh/w-shmice 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.
KEY WORDS: Tacrolimus, MRGPRX2/B2, mast cell, inflammation,
itching