The Duffy Antigen Receptor for Chemokines (DARC) Regulates Asthma Pathophysiology

Abstract

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 three 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 analyzed 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=0.0062).

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.

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