Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 134, Issue 5, Pages 1163-+Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2014.04.035
Keywords
Myeloid-derived suppressor cells; aspirin-intolerant asthma; T(H)2; COX; prostaglandin; arginase
Categories
Funding
- Ministry of Science and Technology of China [2012CB945100, 2011CB503906, 2011ZX09307-302-01, 2012CB524900, 2012BAK01B00]
- National Natural Science Foundation of China [81030004, 81072397, 31200860, 31270921]
- NSFC-CIHR [81161120538/CCI117951]
- Knowledge Innovation Program [KSCX2-EWR-09]
- Shanghai Institutes for Biological Sciences of the Chinese Academy of Sciences [2012KIP514]
- Clinical Research Center at Institute for the Nutritional Sciences, Shanghai Institutes for Biological Sciences [CRC2010007]
- Natural Science Foundation of Guangdong [S2011020006072]
- Guangdong Innovative Research Team Program [2009010058]
- Program of the Chinese Academy of Sciences [2010OHTP10]
- Pujiang Talents Program of Shanghai Municipality [11PJ1411100]
- Heart and Stroke Foundation of Ontario [HSF CI-7406]
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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 T(H)2 airway responses. The T(H)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 E-2 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 E-2/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.
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