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

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:137

Article

Buchheit, Kathleen M.^1,3  Cahill, Katherine N.^1,3  Katz, Howard R.^1,3  Murphy, Katherine C.³  Feng, Chunli³  Lee-Sarwar, Kathleen¹  Lai, Juying³  Bhattacharyya, Neil^2,4  Israel, Elliot^1,5  Boyce, Joshua A.^1,3  Laidlaw, Tanya M.^1,3 

[1] Harvard Univ, Sch Med, Dept Med, Boston, MA USA

[2] Harvard Univ, Sch Med, Dept Surg, Boston, MA 02115 USA

[3] Brigham & Womens Hosp, Div Rheumatol Allergy & Immunol, 75 Francis St, Boston, MA 02115 USA

[4] Brigham & Womens Hosp, Div Otolaryngol, 75 Francis St, Boston, MA 02115 USA

[5] Brigham & Womens Hosp, Div Pulm Med, 75 Francis St, Boston, MA 02115 USA

关键词: Aspirin-exacerbated respiratory disease;    Samter triad;    nasal polyps;    thymic stromal lymphopoietin;    prostaglandin D-2;    cysteinyl leukotrienes;    innate immunity;    mast cells;    eosinophils;   

DOI  :  10.1016/j.jaci.2015.10.020

来源: Elsevier

【 摘 要 】

Background: Prostaglandin (PG) D-2 is the dominant COX product of mast cells and is an effector of aspirin-induced respiratory reactions in patients with aspirin-exacerbated respiratory disease (AERD). Objective: We evaluated the role of the innate cytokine thymic stromal lymphopoietin (TSLP) acting on mast cells to generate PGD(2) and facilitate tissue eosinophilia and nasal polyposis in patients with AERD. Methods: Urinary eicosanoid levels were measured in aspirin-tolerant control subjects and patients with AERD. Nasal polyp specimens from patients with AERD and chronic rhinosinusitis were analyzed by using quantitative PCR, Western blotting, and immunohistochemistry. Human cord blood-and peripheral blood-derived mast cells were stimulated with TSLP in vitro to assess PGD(2) generation. Results: Urinary levels of a stable PGD(2) metabolite (uPGD-M) were 2-fold higher in patients with AERD relative to those in control subjects and increased further during aspirin-induced reactions. Peak uPGD-Mlevels 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 PGD(2) synthase (hematopoietic PGD(2) synthase) mRNA at higher levels than did eosinophils from the same tissue. Whole nasal polyp TSLP mRNA expression correlated strongly with mRNA encoding hematopoietic PGD(2) synthase (r = .75), the mast cell-specific marker carboxypeptidase A3 (r = .74), and uPGD-M (r=0.74). Levels of the cleaved active form of TSLP were increased in nasal polyps from patients with AERD relative to those in aspirin-tolerant control subjects. Recombinant TSLP induced PGD(2) generation by cultured human mast cells. Conclusions: Our study demonstrates that mast cell-derived PGD(2) 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.

【 授权许可】

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