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