Introduction (3755)
Tacrolimus, a 23-member macrolide produced by streptomyces tsukabaensis, is a potent immunosuppressant. It mainly suppresses the responsiveness of T lymphocytes to antigens by forming an FK506-binding protein/tacrolimus complex to inhibit calcineurin, as well as inhibits the release of inflammatory mediators from mast cells and basophils, and downregulates the expression of IL-8 receptor and FcεRI on Langerhans cell, which is important in many inflammatory diseases1. Currently, for its potent effects as immunosuppressant and anti-inflammation, topical tacrolimus has been used in the treatment of various chronic skin diseases, such as atopic dermatitis (AD), allergic contact dermatitis (ACD), lichen planus and psoriasis, etc2. Actually, tacrolimus could reduce the inflammatory reaction and chronic pruritus in AD and psoriasis.
MCs play important roles in allergic and inflammatory diseases3,4. Classically, IgE-dependent MC activation is the main mechanism in allergy. However, chronic pruritus in AD and psoriasis is mainly mediated by non-lgE dependent pathway5. Besides, more and more researchers have emphasized the importance of this non-lgE dependent pathway of MC stimulation and its role in persistent chronic skin inflammation and disease exacerbation6. Traditionally, tacrolimus could inhibit IgE-dependent MCs activation. Recently, it has been reported that topical tacrolimus could alleviate itch-scratch circle via blocking sensory nerve fibers elongation and desensitization as well as pruritus mediator IL-31 in chronic inflammatory pruritic skin disease7-9 . However, the effect of tacrolimus on IgE-independent MCs activation has not been detected.
Notably, side effects such as mild to moderate skin irritation, itching, and burning induced by topical tacrolimus application often occur rapidly in the first few days and fade hereafter, which is similar to drug pseudo-allergy reaction10,11. Pseudo-allergic reaction often manifests as transient itching, skin flushing and vascular permeability in a dose-dependent manner12,13.
Mas-related G protein-coupled receptor-X2 (MRGPRX2), expressed on mast cells, has been identified as a main receptor mediating pseudo-allergic reaction14. MRGPRX2 (or its murine equivalent MrgprB2) can be activated by multiple agonists such as mastoparan, substance P (SP) , compound 48/80 (C48/80), and some FDA approved drugs15. Compared to IgE dependent signaling pathway, MRGPRX2 activates MCs degranulation in a non-IgE dependent manner with more tryptase released instead of histamine16. Growing findings indicate MRGPRX2 on MCs may play a pivotal role in the pathological process of chronic inflammatory and pruritic skin diseases14,17. Recently reinforced by insights into the structure of MRGPRX2, MRGPRX2 can be identified as a crucial therapeutic target for chronic inflammatory dermatitis and itch18.
Together, it seems paradoxical that tacrolimus induces initial inflammation meanwhile as an immunosuppressant suppressor. Our hypothesis is that MRGPRX2 in MCs is a vital target for tacrolimus dual effect to activate and suppress the MCs mediated inflammation in skin with time dependent way.