title: Myeloid-derived suppressor cell function is diminished in aspirin-triggered allergic airway hyperresponsiveness in mice.
abstract: 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(+)Gr1(high)Ly6G(+)Ly6C(int) 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 TH2 airway responses. The TH2-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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China.
authors.forename: Maohua
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Guochao
authors.initials: G
authors.lastname: Shi
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Tang
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Deping
authors.initials: D
authors.lastname: Kong
authors.affiliation: Department of Pulmonary Medicine, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Bao
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Xiao
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Caojian
authors.initials: C
authors.lastname: Zuo
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Tai
authors.initials: T
authors.lastname: Wang
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yujun
authors.initials: Y
authors.lastname: Shen
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Biomedical and Molecular Sciences, Queen's University, Kingston, Ontario, Canada.
authors.forename: Colin D
authors.initials: CD
authors.lastname: Funk
authors.affiliation: Institute of Human Virology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou, China; Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Chinese Ministry of Education, Guangzhou, China. Electronic address: zhouj72@mail.sysu.edu.cn.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China; Key Laboratory of Food Safety Risk Assessment, Ministry of Health, Beijing, China. Electronic address: yuying@sibs.ac.cn.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yu
mesh_terms: D000485:Allergens / Q000633:toxicity; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D001119:Arginase / Q000235:genetics / Q000276:immunology; D001241:Aspirin / Q000009:adverse effects / Q000494:pharmacology; D055963:Asthma, Aspirin-Induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000276:immunology; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D058307:Receptors, Prostaglandin E, EP2 Subtype / Q000235:genetics / Q000276:immunology; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology / Q000473:pathology
chemical_list: D000485:Allergens; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000943:Antigens, Differentiation; D008565:Membrane Proteins; D058307:Receptors, Prostaglandin E, EP2 Subtype; D058309:Receptors, Prostaglandin E, EP4 Subtype; D051545:Cyclooxygenase 1; C496512:Ptgs1 protein, mouse; D017868:Cyclic AMP-Dependent Protein Kinases; C544448:Arg1 protein, mouse; D001119:Arginase; D001241:Aspirin
keywords: COX; Myeloid-derived suppressor cells; T(H)2; arginase; aspirin-intolerant asthma; prostaglandin