Thimerosal induces skin pseudo-allergic reaction via Mas-related G-protein coupled receptor B2

Abstract

Background: Thimerosal has been used as a preservative in many products which may cause contact dermatitis. It is the second most common allergen in positive patch test reactions, though being a clinical irrelevant allergen. Thimerosal-induced contact dermatitis is generally considered to be a delayed-type hypersensitivity reaction, but it is difficult to explain the fact that most patients develop an allergic reaction upon first encounter with thimerosal. Recent studies have demonstrated the association between Mas-related G protein coupled receptor X2 (MRGPRX2) and pseudo-allergic reactions which occur at the first contact with stimulation. This suggests the possibility that thimerosal may cause contact dermatitis via MRGPRX2 mediated mechanism. Objectives: To investigate the role of Mas-related G-protein coupled receptor B2 (MrgprB2)/MRGPRX2 in contact dermatitis induced by thimerosal. Methods: Thimerosal induced pseudo-allergic reactions via MrgprB2/ MRGPRX2 were investigated using a novel skin pseudo-allergic reaction mouse model, footpad swelling and extravasation assays in vivo and mast cell degranulation assay in vitro. Results: Thimerosal induced contact dermatitis in dorsal skin and footpad swelling in wild-type mice, but had no significant effect in MrgprB2-knockout mice. Thimerosal-induced dermatitis is characterized by infiltration of inflammatory cells and elevation of serum histamine and inflammatory cytokines, rather than elevation of serum IgE level. Thimerosal increased the intracellular Ca 2+ concentration in HEK293 cells overexpressing MrgprB2/MRGPRX2. Downregulation of MRGPRX2 resulted in the reduced degranulation of LAD2 human mast cells. Conclusions: MrgprB2 mediates thimerosal-induced mast cell degranulation and pseudo-allergic reaction in mice. MRGPRX2 may be a key contributor to human contact dermatitis.

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

“…On the other hand, recent studies on the pathophysiology of ACD have also reported that the production of cytokines and chemokines by MC activation plays a major role in the magnitude of the inflammatory response mediated by CD8 + T cells [ 95 ]. Mrgprb2-KO mice have been reported to have significantly reduced inflammation, including itching in various models of allergic contact dermatitis [ 97 , 98 , 99 ], suggesting that MRGPRX2 is involved in the development of ACD as well as atopic dermatitis.…”

Natural and Conventional Cosmetics—Mercury Exposure Assessment

“…The relationship between the presence of Thiomersal and a pseudoallergic skin reaction was investigated by Peng et al (2019) [ 42 ]. The study showed that MrgprB2/MRGPRX2 had an effect on Thimerosal-induced mast cell degranulation as well as the pseudoallergic response in mice—thus, it may play an important role in contact dermatitis in humans.…”

The Multifaceted Mas-Related G Protein-Coupled Receptor Member X2 in Allergic Diseases and Beyond

“…A new connection is being discovered between MRGPRX2 and contact dermatitis. Peng et al discovered that thimerosal, a preservative known for inducing contact dermatitis, is capable of inducing mast cell degranulation and increase of calcium concentration in HEK293 cells transfected with either MRGPRX2 or mrgprb2, and that LAD2 cells with a downregulated receptor showed reduced degranulation when exposed to the agent [72]. Presence of thimerosal induces contact dermatitis in dorsal skin and footpad swelling of mice with a normal receptor, an effect that is attenuated when the receptor is knocked out [72].…”

“…Peng et al discovered that thimerosal, a preservative known for inducing contact dermatitis, is capable of inducing mast cell degranulation and increase of calcium concentration in HEK293 cells transfected with either MRGPRX2 or mrgprb2, and that LAD2 cells with a downregulated receptor showed reduced degranulation when exposed to the agent [ 72 ]. Presence of thimerosal induces contact dermatitis in dorsal skin and footpad swelling of mice with a normal receptor, an effect that is attenuated when the receptor is knocked out [ 72 ]. Interestingly, the receptor seems to mediate both an immediate, non-IgE reaction as well as a delayed hypersensitivity-type reaction in mice, evidence that the receptor has multiple capabilities in distinct types of hypersensitivities.…”

“…Interestingly, the receptor seems to mediate both an immediate, non-IgE reaction as well as a delayed hypersensitivity-type reaction in mice, evidence that the receptor has multiple capabilities in distinct types of hypersensitivities. Furthermore, the pseudo-allergic reactions induced by thimerosal have been shows to be dose-dependent, both in terms of presence of edema and vasodilation [ 72 ], a factor that sheds light on the receptor’s role in certain drug hypersensitivity reactions, which seem to remain under control when infusion rate is changed, as with vancomycin [ 56 ].…”