Mast cell-MrgprB2: sensing secretagogues or a means to overreact?

Abstract

Mast cells are unique immunocytes that reside predominantly at anatomical sites exposed to the environment, such as the skin, gastrointestinal tract and lung. Their strategic location and potential to participate in diverse physiological and pathological processes, as a result of their activation by any of an array of receptors, indicates that they can act as key contributors of innate and adaptive immune responses, inflammation and tissue remodelling.1, 2 Despite their beneficial functions of maintaining homeostasis1 and acting as sentinels in host defence, mast cells have earned notoriety as troublesome cells owing to their detrimental contributions in IgE-mediated allergic disorders. In such settings mast-cell activation is initiated when antigen cross-links antigen-specific IgE antibodies bound to high-affinity FceRI receptors.2 In addition to this classical mode of activation, mast cells also respond to basic secretagogues, including Substance P, mastoparan and compound 48/80, as well as a range of peptidergic drugs associated with adverse reactions.3, 4, 5 Basic polycationic peptides are thought to activate pertussis toxin-sensitive G proteins (that is, Gi2 and Gi3) in a receptor-independent manner on the mast cell surface.6 These in turn propagate signalling via pathways involving phospholipase C-γ, phosphatidylinositol 3-kinase and phospholipase A2, which then promote Ca2+ mobilisation that leads to exocytosis of preformed granule-associated mediators (for example, histamine) and the synthesis of arachidonic acid metabolites.6 However, the specific molecular mechanisms underlying basic secretagogue or peptide-induced activation of mast cell G proteins or a receptor, particularly those involved in drug-associated anaphylactoid/pseudoallergic reactions, have been poorly understood until now.