Typical antimicrobials induce mast cell degranulation and anaphylactoid reactions via MRGPRX2 and its murine homologue MRGPRB2

Abstract

Mast cells are unique immune cells that function as sentinels in host defence reactions, including immediate hypersensitivity responses and allergic responses. The mast cell-specific receptor named MAS-related G protein-coupled receptor X2 (MRGPRX2) triggers mast-cell degranulation, a key process in anaphylactoid reactions. It is widely observed that antimicrobials can induce pseudo-allergic reactions (i.e. IgE-independent mechanism) with symptoms ranging from skin inflammation to life-threatening systemic anaphylaxis. However, their direct involvement and the mechanisms underlying anaphylactoid reactions caused by antimicrobials have not been demonstrated. Structurally different antimicrobials were screened by Ca imaging using MRGPRX2 overexpressing HEK293 cells. MRGPRX2 related anaphylactoid reactions induced by these components were investigated by body temperature drop and mast cell degranulation assays. We showed that MRGPRX2 is involved in allergic-like reactions to three types of antimicrobials in a dose-dependent manner. However, mast cells lacking the receptor show reduced degranulation. Furthermore, mice without MAS-related G protein-coupled receptor B2 (the orthologous gene of MRGPRX2) exhibited reduced substance-induced inflammation. Interestingly, β-lactam and antiviral nucleoside analogues did not induce anaphylactic reactions, which were also observed in vitro. These results should alarm many clinicians that such drugs might induce anaphylactoid reactions and provide guidance on safe dosage of these drugs.

Paeoniflorin inhibits MRGPRX2‐mediated pseudo‐allergic reaction via calcium signaling pathway

“…Some reports have also provided evidence that PF can treat anaphylactic rhinitis and allergic asthma (Gaudenzio et al, ). Activation of MRGPRX2 can induce the release of several proinflammatory mediators including, interleukins, tumor necrosis factor, and prostaglandin D2 which can induce itch (Zhang et al, ). MRGPRX2 showed a correlation to two specific itchy conditions, namely, red man syndrome associated with vancomycin and atopic dermatitis (Azimi, Reddy, & Lerner, ).…”

A humanized mouse model to study mast cells mediated cutaneous adverse drug reactions

“…Recently, the receptor on MCs that specifically binds non‐immune ADR‐causing drugs was reported to be MRGPRX2, a G protein‐coupled receptor found almost exclusively on MCs . The mouse analogue of this receptor is Mrgprb2, which is found mostly on connective tissue MCs . Although several drugs have been reported to cause adverse reactions in humans, only few have been shown to evoke a similar reaction in mice .…”

Discovery and analysis the anti-pseudo-allergic components from Perilla frutescens leaves by overexpressed MRGPRX2 cell membrane chromatography coupled with HPLC-ESI-IT-TOF system

“…In 2015, XZ Dong et al . first found that Mas‐related G protein‐coupled receptor X2 (MRGPRX2) specific expressed on mast cells was related to pseudo‐allergic reactions and could be used as a potential target for therapy . Basing on the previous research, PF has been proved to be effective in alleviating allergic or pseudo‐allergic reaction, however, whether it exerted the anti‐pseudo‐allergic pharmacological effects by targeting to MRGPRX2 receptor remains unknown.…”