Recent advances in mast cell activation and regulation

Abstract

Mast cells are innate immune cells that intersect with the adaptive immunity and play a crucial role in the initiation of allergic reactions and the host defense against certain parasites and venoms. When activated in an allergen- and immunoglobulin E (IgE)-dependent manner, these cells secrete a large variety of allergenic mediators that are pre-stored in secretory granules or de novo-synthesized. Traditionally, studies have predominantly focused on understanding this mechanism of mast cell activation and regulation. Along this line of study, recent studies have shed light on what structural features are required for allergens and how IgE, particularly anaphylactic IgE, is produced. However, the last few years have seen a flurry of new studies on IgE-independent mast cell activation, particularly via Mrgprb2 (mouse) and MRGPRX2 (human). These studies have greatly advanced our understanding of how mast cells exert non-histaminergic itch, pain, and drug-induced pseudoallergy by interacting with sensory neurons. Recent studies have also characterized mast cell activation and regulation by interleukin-33 (IL-33) and other cytokines and by non-coding RNAs. These newly identified mechanisms for mast cell activation and regulation will further stimulate the allergy/immunology community to develop novel therapeutic strategies for treatment of allergic and non-allergic diseases.

Keywords: Allergy; FcεRI; IL-33; IgE; MRGPRX2; allergen; mast cells; miRNA.

Figure 1.. Mechanisms underlying response to cyclooxygenase 1 (COX-1) inhibitors in patients with aspirin-exacerbated respiratory disease (AERD)

Patients with AERD show lower levels of COX-2 compared with the healthy population. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX-1 and lower the level of prostaglandin E ₂ (PGE ₂). The loss of PGE ₂ inhibitory control leads to massive release of histamine and generation of cysteinyl leukotrienes by mast cells, an event that is unique to AERD. Red arrows represent abnormal baseline conditions in patients with AERD, and blue arrows indicate changes after COX-1 inhibition. The size of the arrows indicates the magnitude of change. 5-HPETE, 5-hydroperoxyeicosatetraenoic acid; 5-LO, 5-lipoxygenase; LT, leukotriene (A4, C4, D4, and E4); PG, prostaglandin (G2, H2, I2, and F2); TXA2, thromboxane A2.