Updates on immune mechanisms in aspirin-exacerbated respiratory disease

Abstract

Aspirin-exacerbated respiratory disease has fascinated and frustrated specialists in allergy/immunology, pulmonology, and otorhinolaryngology for decades. It generally develops in previously healthy young adults and is unremitting and challenging to treat. The classical triad of asthma, nasal polyposis, and pathognomonic respiratory reactions to aspirin and other cyclooxygenase-1 inhibitors is accompanied by high levels of mast cell activation, cysteinyl leukotriene production, platelet activation, and severe type 2 respiratory inflammation. The "unbraking" of mast cell activation and further cysteinyl leukotriene generation induced by cyclooxygenase-1 inhibition reflect an idiosyncratic dependency on cyclooxygenase-1-derived products, likely prostaglandin E₂, to maintain a tenuous homeostasis. Although cysteinyl leukotrienes are clear disease effectors, little else was known about their cellular sources and targets, and the contributions from other mediators and type 2 respiratory inflammation effector cells to disease pathophysiology were unknown until recently. The applications of targeted biological therapies, single-cell genomics, and transgenic animal approaches have substantially advanced our understanding of aspirin-exacerbated respiratory disease pathogenesis and treatment and have also revealed disease heterogeneity. This review covers novel insights into the immunopathogenesis of aspirin-exacerbated respiratory disease from each of these lines of research, including the roles of lipid mediators, effector cell populations, and inflammatory cytokines, discusses unanswered questions regarding cause and pathogenesis, and considers potential future therapeutic options.

Keywords: AERD; CRSwNP; leukotriene E4; mast cells; mechanisms; prostaglandin E2.

Figure 1.. Summary of the pathogenesis of the chronic inflammation in the respiratory tissue in AERD.

IL-33 and TSLP derived from dysplastic epithelial basal cells activate Th2 cells and ILC2s to produce IL4, IL-13, and IL-5, as well as activating mast cells. Those cytokines in turn activate and recruit B cells, plasma cells, mast cells and eosinophils and also feedback to target the epithelium. Proinflammatory lipids CysLTs and PGD₂ are overproduced and act in concert with IL-33 to activate ILC2s, the anti-inflammatory lipid, PGE₂, is underproduced, contributing to ILC2 expansion and unchecked mast cell activation. ILC, innate lymphoid cell; CysLT, cysteinyl leukotriene; PG, prostaglandin; TSLP, thymic stromal lymphopoietin