Thymic Stromal Lymphopoietin Controls Prostaglandin D2 Generation in Aspirin-Exacerbated Respiratory Disease

Rationale: 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). 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 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 increases in nasal congestion. Mast cells sorted from nasal polyps expressed PGD₂ synthase (hPGDS) mRNA at higher levels than did eosinophils sorted from the same tissue. Whole nasal polyp TSLP mRNA expression correlated 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 system contributes to the pathophysiology of AERD.