Myeloid-derived suppressor cell function is diminished in aspirin-triggered allergic airway hyperresponsiveness in mice

• Published in: Journal of allergy and clinical immunology Vol. 134; no. 5; pp. 1163 - 1174.e16
• Main Authors: Shi, Maohua, MD, Shi, Guochao, MD, PhD, Tang, Juan, BSc, Kong, Deping, BSc, Bao, Yao, MD, Xiao, Bing, MSc, Zuo, Caojian, MD, Wang, Tai, Wang, Qingsong, PhD, Shen, Yujun, PhD, Wang, Hui, MD, PhD, Funk, Colin D., PhD, Zhou, Jie, MD, PhD, Yu, Ying, MD, PhD
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.11.2014; Elsevier; Elsevier Limited
• Subjects: Allergens - toxicity; Allergy and Immunology; Animals; Anti-Inflammatory Agents, Non-Steroidal - adverse effects; Anti-Inflammatory Agents, Non-Steroidal - pharmacology; Antigens, Differentiation - genetics; Antigens, Differentiation - immunology; arginase; Arginase - genetics; Arginase - immunology; Aspirin; Aspirin - adverse effects; Aspirin - pharmacology; aspirin-intolerant asthma; Asthma; Asthma, Aspirin-Induced - genetics; Asthma, Aspirin-Induced - immunology; Asthma, Aspirin-Induced - pathology; Biological and medical sciences; Chronic obstructive pulmonary disease, asthma; COX; Cyclic AMP-Dependent Protein Kinases - genetics; Cyclic AMP-Dependent Protein Kinases - immunology; Cyclooxygenase 1 - genetics; Cyclooxygenase 1 - immunology; Cytokines; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Humans; Immune Tolerance; Immunopathology; Laboratories; Medical sciences; Membrane Proteins - genetics; Membrane Proteins - immunology; Mice; Mice, Knockout; Myeloid Cells - immunology; Myeloid Cells - pathology; Myeloid-derived suppressor cells; Nonsteroidal anti-inflammatory drugs; Pathogenesis; Pneumology; Population; prostaglandin; Proteins; Receptors, Prostaglandin E, EP2 Subtype - genetics; Receptors, Prostaglandin E, EP2 Subtype - immunology; Receptors, Prostaglandin E, EP4 Subtype - genetics; Receptors, Prostaglandin E, EP4 Subtype - immunology; Rodents; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - immunology; Software; TH2; Th2 Cells - immunology; Th2 Cells - pathology; Protein kinase A; MDSC; TX; Myeloid-derived suppressor cells; AHR; Mice sensitized with Ef-OVA and low-dose LPS (0.1 μg) and challenged with Ef-OVA; arginase; T H2; Mo-MDSC; Bone marrow; AIA; Monocytic MDSC; Arg1; prostaglandin; PKA; Cyclic AMP; EP; aspirin-intolerant asthma; Wild-type; Airway hyperresponsiveness; Arginase-1; E prostanoid receptor; Nitric oxide; Nonsteroidal anti-inflammatory drug; ROS; Bronchoalveolar lavage fluid; L-NMMA; OVA; NO; L-N G-monomethyl arginine; Reactive oxygen species; Aspirin-tolerant asthma; Endotoxin-free ovalbumin; NSAID; BM; cAMP; CREB; cAMP response element-binding protein; PMN-MDSC; 5-Carboxyfluorescein diacetate succinimidyl ester; Allophycocyanin; Polymorphonuclear MDSC; WT; Ef-OVA; Myeloid-derived suppressor cell; Ovalbumin; KO; BALF; CFSE; Ef-OVA LPS/Ef-OVA mice; COX; ATA; Knockout; APC; PE; Phycoerythrin; PG; Thromboxane; Ef-OVALPS/Ef-OVA mice; TH2; Prostaglandin-endoperoxide synthase; Allergy; Hyperreactivity; Myeloid derived suppressor cell; Arginase; Acetylsalicylic acid; Respiratory system; Respiratory tract; Immunology; T; Eicosanoid; T-Lymphocyte; Bronchus disease; Th2 lymphocyte; Obstructive pulmonary disease; Salicylates; Lung disease; Immunopathology; Prostaglandin; Enzyme; Respiratory disease; Arachidonic acid derivatives; Rodentia; Enzyme inhibitor; Antiplatelet agent; Asthma; Vertebrata; 2; Mammalia; Mouse; Animal; Hydrolases; Oxidoreductases; T(H)2
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2014.04.035

Background Myeloid-derived suppressor cells (MDSCs) have recently been implicated in the pathogenesis of asthma, but their regulation in patients with aspirin-intolerant asthma (AIA) remains unclear. Objective We sought to characterize MDSC accumulation and pathogenic functions in allergic airway inflammation mediated by COX-1 deficiency or aspirin treatment in mice. Methods Allergic airway inflammation was induced in mice by means of ovalbumin challenge. The distribution and function of MDSCs in mice were analyzed by using flow cytometry and pharmacologic/gene manipulation approaches. Results CD11b+ Gr1high Ly6G+ Ly6Cint MDSCs (polymorphonuclear MDSCs [PMN-MDSCs]) recruited to the lungs are negatively correlated with airway inflammation in allergen-challenged mice. Aspirin-treated and COX-1 knockout (KO) mice showed significantly lower accumulation of PMN-MDSCs in the inflamed lung and immune organs accompanied by increased TH 2 airway responses. The TH 2-suppressive function of PMN-MDSCs was notably impaired by COX-1 deletion or inhibition, predominantly through downregulation of arginase-1. COX-1–derived prostaglandin E2 promoted PMN-MDSC generation in bone marrow through E prostanoid 2 and 4 receptors (EP2 and EP4), whereas the impaired arginase-1 expression in PMN-MDSCs in COX-1 KO mice was mediated by dysregulation of the prostaglandin E2 /EP4/cyclic AMP/protein kinase A pathway. EP4 agonist administration alleviated allergy-induced airway hyperresponsiveness in COX-1 KO mice. Moreover, the immunosuppressive function of PMN-MDSCs from patients with AIA was dramatically decreased compared with that from patients with aspirin-tolerant asthma. Conclusion The immunosuppressive activity of PMN-MDSCs was diminished in both allergen-challenged COX-1 KO mice and patients with AIA, probably through an EP4-mediated signaling pathway, indicating that activation of PMN-MDSCs might be a promising therapeutic strategy for asthma, particularly AIA.