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.