Thymic stromal lymphopoietin controls prostaglandin D2 generation in patients with aspirin-exacerbated respiratory disease

Abstract

Background Prostaglandin D2 (PGD2) is the dominant cyclooxygenase product of mast cells and is an effector of aspirin-induced respiratory reactions in aspirin-exacerbated respiratory disease (AERD). Objective We evaluated the role of the innate cytokine thymic stromal lymphopoietin (TSLP) acting on mast cells to generate PGD2 and facilitate tissue eosinophilia and nasal polyposis in AERD. Methods Urinary eicosanoids were measured in aspirin-tolerant controls and patients with AERD. Nasal polyp specimens from subjects with AERD and chronic rhinosinusitis were analyzed via qPCR, western blot, and immunohistochemistry. Human cord blood-derived and peripheral blood-derived mast cells were stimulated with TSLP in vitro to assess PGD2 generation. Results Urinary levels of a stable PGD2 metabolite (uPGD-M) were 2-fold higher in subjects with AERD relative to controls, and increased further during aspirin-induced reactions. Peak uPGD-M levels during aspirin reactions correlated with reductions in blood eosinophil counts and lung function, and with increases in nasal congestion. Mast cells sorted from nasal polyps expressed PGD2 synthase (hPGDS) mRNA at higher levels than did eosinophils from the same tissue. Whole nasal polyp TSLP mRNA expression correlated strongly with mRNA encoding hPGDS (r = .75), the mast cell-specific marker carboxypeptidase A3 (r = .74), and uPGD-M (r=0.74). The cleaved, active form of TSLP was increased in AERD nasal polyps relative to aspirin-tolerant controls. Recombinant TSLP induced PGD2 generation by cultured human mast cells. Conclusions Our study demonstrates that mast cell-derived PGD2 is a major effector of type 2 immune responses driven by TSLP, and suggests that dysregulation of this innate system contributes significantly to the pathophysiology of AERD.

Group 2 innate lymphoid cells are recruited to the nasal mucosa in patients with aspirin-exacerbated respiratory disease

“…Buchheitt et al reported that increased nasal symptoms in AERD correlated with peak levels of a PGD2 metabolite which could promote ILC2 recruitment and activation (7). These data also indicate that subjective patient symptoms, particularly naso-ocular symptoms, can be correlated with objective laboratory measurements of reaction intensity.…”

“…Indeed, one mechanism by which aspirin desensitization may work is by preventing cells from homing into the tissues (29). PGD2 is increased in mast cells from patients with AERD (7) and high doses of aspirin are able to block both COX-1 and COX-2, which may allow for prevention of high amounts of PGD2. Cahill et al showed that, PGD2 decreases after aspirin desensitization and blood eosinophils actually increase in the blood over time (29), presumably due to loss of the PGD2 gradient.…”

“…The disease is characterized by release of large amounts of cysteinyl leukotrienes (CysLTs) and mast cells mediators, particularly prostaglandin D2 (PGD2), after COX-1 inhibitor ingestion (5, 6). Recently, thymic stromal lymphopoietin (TSLP) and IL-33 have also been implicated in AERD pathogenesis (7, 8). These two cytokines, in addition to PGD2 and CysLTs, are known to promote group 2 innate lymphoid cell (ILC2) activation (9-12) and their presence suggests that ILC2s may be active in AERD.…”

Aspirin-Exacerbated Respiratory Disease as an Endotype of Chronic Rhinosinusitis

“…Walford and colleagues reported an overall correlation between the number of eosinophils and ILC2s in nasal polyps but they did not specifically compare ILC2 numbers in AERD versus CRSwNP nasal polyps 50 . Similar to eosinophils, mast cell numbers did not significantly differ between CRSwNP and AERD nasal polyps 41, 52 . However, mast cells are a major source of prostaglandin D2 (PGD 2 ) and this inflammatory mediator has been shown to be significantly elevated in AERD compared to CRSwNP patients, especially after aspirin challenge 52, 53 .…”

“…Similar to eosinophils, mast cell numbers did not significantly differ between CRSwNP and AERD nasal polyps 41, 52 . However, mast cells are a major source of prostaglandin D2 (PGD 2 ) and this inflammatory mediator has been shown to be significantly elevated in AERD compared to CRSwNP patients, especially after aspirin challenge 52, 53 . Finally, basophil numbers were significantly reduced in AERD versus CRSwNP nasal polyps 46 .…”