Cellular interactions in aspirin-exacerbated respiratory disease

Abstract

Purpose of review The purpose of this review is to summarize the complex cellular interactions of aspirin-exacerbated respiratory disease (AERD) and how these interactions promote pathogenic mechanisms of AERD. Recent findings In addition to characteristic changes in eicosanoid levels, recent studies have identified increases in alarmin cytokines (IL-33, thymic stromal lymphopoietin) as well as activated innate lymphoid and plasma cell populations in samples from AERD patients. Summary Patients with AERD typically demonstrate high levels of proinflammatory eicosanoids including cysteinyl leukotrienes (CysLTs) and prostaglandin D2 (PGD2) and hyporesponsiveness to prostaglandin E2 (PGE2). CysLTs are released by mast cells, eosinophils, and adherent platelets and promote epithelial release of IL-33, which activates mast cells and group 2 innate lymphoid cells (ILC2s) in concert with CysLTs. TSLP induces PGD2 release from mast cells which activates and recruits eosinophils, basophils, Th2 cells, and ILC2s via CRTH2. In turn, ILC2s and other cell types produce Th2 cytokines IL-4, IL-5, and IL-13 that, along with CysLTs and PGD2, promote bronchoconstriction, eosinophilic tissue inflammation, and mucus production.

Pathomechanisms of AERD—Recent Advances

“…Eosinophils, abundant in nasal polyps, bronchial mucosa, and peripheral blood, produce PGD 2 and are attracted to PGD 2 by chemotaxis ( 40 ). Choi et al found that eosinophils interact with epithelial cells through surfactant protein D, and may mediate smooth muscle remodeling, a clinical feature of AERD ( 41 ).…”

“…The three first mentioned may stimulate plasma cells to produce IgE and IgG4. IL-5 also promotes recruitment, survival and activation of eosinophils and IL-9 may increase the amount of mast cells recruited to the tissue ( 40 ). Several prostaglandins also regulate ILC2 function.…”

“…Several prostaglandins also regulate ILC2 function. PGD 2 activates ILC2s and induces chemotaxis and cytokine production, whereas PGE 2 and PGI 2 have inhibitory actions ( 40 ). During aspirin desensitization, ILC2s in nasal fluid increased in correlation with symptom scores and with increases in PGD 2 metabolites in urine, indicating a potential connection between PGD 2 release, ILC2 recruitment, and symptom severity during aspirin-induced reactions in AERD ( 44 ).…”

Reprogramming of arachidonic acid metabolism using α-terpineol to alleviate asthma: insights from metabolomics

“…36 Leukotrienes can cause the accumulation of large numbers of leucocytes and other inflammatory cells, which can lead to contraction of airway smooth muscle, increased vascular permeability and mucus secretion. 37,38 Some other inflammatory mediators also activate CysLTs. 39 Furthermore, CysLTs interact with other inflammatory mediators to amplify the cascade of inflammatory responses and promote disease progression.…”

Lower serum 15-HETE level predicts nasal ILC2 accumulation during COX-1 inhibition in AERD

“… 2 – 6 AERD pathogenesis involves interactions with several immune cellular players, including mast cells, eosinophils, basophils, T cells, and group 2 innate lymphoid cells (ILC2s). 7 , 8 CysLTs contribute to the release of epithelial IL-33, which can activate mast cells to induce release of PGD 2 . 9 PGD 2 can, in turn, activate eosinophils, basophils, T H 2 cells, and ILC2s by binding to chemoattractant receptor–homologous molecules expressed on T H 2 cells (CRTH2).…”