Identification of a mast-cell-specific receptor crucial for pseudo-allergic drug reactions

Cationic substances, including some drugs, can activate mast cells in an IgE-independent manner, leading to histamine release, inflammation and airway contraction; here, the G-protein-coupled receptor MrgprB2, the orthologue of human MRGPRX2, is shown to be the sole mast cell receptor for these substances in mice. Mast cells, innate immune cells found in most tissues of the body and are active in allergic reactions. Mast cells can be activated in an immunoglobulin-E-independent manner by cationic substances such as pro-inflammatory signalling peptides, therapeutic drugs and components of animal toxins, leading to histamine release, inflammation and airway contraction. Xinzhong Dong and colleagues now show that a single G-protein-coupled receptor called Mrgprb2, the orthologue of human MRGPRX2, is the sole mast cell receptor for these substances in mice. This work identifies MRGPRX2 as a potential therapeutic target to counter a range of drug-induced adverse effects, and Mrgprb2 knockouts and other mice used in the study will provide a model in which to address the role of antibody-independent activation of mast cells in diseases with an allergic component. Mast cells are primary effectors in allergic reactions, and may have important roles in disease by secreting histamine and various inflammatory and immunomodulatory substances1,2. Although they are classically activated by immunoglobulin (Ig)E antibodies, a unique property of mast cells is their antibody-independent responsiveness to a range of cationic substances, collectively called basic secretagogues, including inflammatory peptides and drugs associated with allergic-type reactions1,3. The pathogenic roles of these substances have prompted a decades-long search for their receptor(s). Here we report that basic secretagogues activate mouse mast cells in vitro and in vivo through a single receptor, Mrgprb2, the orthologue of the human G-protein-coupled receptor MRGPRX2. Secretagogue-induced histamine release, inflammation and airway contraction are abolished in Mrgprb2-null mutant mice. Furthermore, we show that most classes of US Food and Drug Administration (FDA)-approved peptidergic drugs associated with allergic-type injection-site reactions also activate Mrgprb2 and MRGPRX2, and that injection-site inflammation is absent in mutant mice. Finally, we determine that Mrgprb2 and MRGPRX2 are targets of many small-molecule drugs associated with systemic pseudo-allergic, or anaphylactoid, reactions; we show that drug-induced symptoms of anaphylactoid responses are significantly reduced in knockout mice; and we identify a common chemical motif in several of these molecules that may help predict side effects of other compounds. These discoveries introduce a mouse model to study mast cell activation by basic secretagogues and identify MRGPRX2 as a potential therapeutic target to reduce a subset of drug-induced adverse effects.