Dual effect of tacrolimus on mast cell–mediated allergy and inflammation through Mas-related G protein-coupled receptor X2

Background

Topical tacrolimus, although widely used in the treatment of dermatoses, presents with an immediate irritation on initial application resembling a pseudo-allergic reaction. Mas-related G protein-coupled receptor X2 (MRGPRX2) in mast cells (MCs) mediates drug-induced pseudo-allergic reaction and immunoglobulin E (IgE)-independent pruritis in chronic skin diseases. However, the immunosuppression mechanism of tacrolimus on MCs via MRGPRX2 has not been reported.

Objective

To investigate the role of MRGPRX2 and the mechanism of action of tacrolimus on its short-term and long-term applications.

Methods

Wild-type mice, Kit^W-sh/W-sh mice, and MrgprB2-deficient (MUT) mice were used to study the effect of tacrolimus on in vivo anaphylaxis model. LAD2 cells and MRGPRX2-knockdown LAD2 cells were specifically used to derive the associated mechanism of the tacrolimus effect.

Results

Short-term application of tacrolimus triggers IgE-independent activation of MCs via MRGPRX2/B2 in both in vivo and in vitro experiments. Tacrolimus binds to MRGPRX2, which was verified by fluorescently labeled tacrolimus in cells. On long-term treatment with tacrolimus, the initial allergic reaction fades away corresponding with the downregulation of MRGPRX2, which leads to decreased release of inflammatory cytokines (P < 0.05 to P < 0.001).

Conclusion

Short-term treatment with tacrolimus induces pseudo-allergic reaction via MRGPRX2/B2 in MCs, whereas long-term treatment downregulates expression of MRGPRX2/B2, which may contribute to its potent immunosuppressive effect in the treatment of various skin diseases.