1. The Duffy antigen receptor for chemokines regulates asthma pathophysiology
- Author
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Chapman, DG, Mougey, EB, Van der Velden, JL, Lahue, KG, Aliyeva, M, Daphtary, N, George, KL, Hoffman, SM, Schneider, RW, Tracy, RP, Worthen, GS, Poynter, ME, Peters, SP, Lima, JJ, Janssen-Heininger, YMW, and Irvin, CG
- Subjects
Male ,Allergy ,Neutrophils ,Gene Expression ,Receptors, Cell Surface ,Respiratory Mucosa ,Severity of Illness Index ,Polymorphism, Single Nucleotide ,Mice ,Leukocytes ,Respiratory Hypersensitivity ,Animals ,Humans ,Antigens, Dermatophagoides ,Mice, Knockout ,Patient Acceptance of Health Care ,Prognosis ,Asthma ,respiratory tract diseases ,Patient Outcome Assessment ,Disease Models, Animal ,Phenotype ,Genetic Loci ,Female ,Disease Susceptibility ,Chemokines ,Duffy Blood-Group System - Abstract
© 2017 John Wiley & Sons Ltd Background: The Duffy antigen receptor for chemokines (DARC) is an atypical receptor that regulates pro-inflammatory cytokines. However, the role of DARC in asthma pathophysiology is unknown. Objective: To determine the role of DARC in allergic airways disease in mice, and the association between DARC single nucleotide polymorphisms (SNPs) and clinical outcomes in patients with asthma. Methods: Mice with targeted disruption of the Darc gene (Darc∆E2) or WT mice were challenged over 3 weeks with house dust mite (HDM) antigen. Allergic airways disease was assessed 24 hours and 7 days following the final challenge. Additionally, associations between DARC SNPs and clinical outcomes were analysed in a cohort of poorly controlled asthmatics. Results: Total airway inflammation following HDM did not differ between Darc∆E2 and WT mice. At 24 hours, Darc∆E2 mice had increased airway hyperresponsiveness; however, at 7 days airway hyperresponsiveness had completely resolved in Darc∆E2 but persisted in WT mice. In poorly controlled asthmatics, DARC SNPs were associated with worse asthma control at randomization and subsequent increased risk of healthcare utilization (odds ratio 3.13(1.37-7.27), P=.0062). Conclusions and Clinical Relevance: Our animal model and human patient data suggest a novel role for DARC in the temporal regulation in asthma pathophysiology and symptoms.
- Published
- 2017