The Duffy antigen receptor for chemokines 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 (DarcΔE2) 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 DarcΔE2 and WT mice. At 24 hours, DarcΔE2 mice had increased airway hyperresponsiveness; however, at 7 days airway hyperresponsiveness had completely resolved in DarcΔE2 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.

House Dust Mite Allergy Under Changing Environments

“…Migration studies have revealed that East Asian populations may be more susceptible to allergy and especially to HDM sensitization 6122. Some African-descent populations have also shown susceptibility alleles for increased IgE levels123 that are of relevance in HDM responses 124. It is thought that global environmental changes will modify the distribution and allergenicity of HDMs, which may increase HDM sensitization by allowing new contexts of HDM exposure.…”

The Duffy antigen receptor for chemokines, ACKR1,– ‘Jeanne DARC’ of benign neutropenia

“…Accordingly, benign neutropenia among Yemenite Jews has been suggested as producing a protective effect against atherosclerotic disease (Ernst et al , ). In addition, ACKR1was found to have a role in asthma pathophysiology both in a mouse model and in a group of poorly controlled asthmatics, in which ACKR1 SNPs were associated with worse asthma control (Chapman et al , ). The ACKR1 genotype was not found to be significantly associated with Behçet disease (Pittoni et al , ).…”

Developments in the field of allergy in 2020 through the eyes of Clinical and Experimental Allergy

“…Chapman and colleagues employed DARC knockout (DARC ΔE2 ) mice to examine the contribution this molecule to the development of AAD. 77 The authors show that house dust mite (HDM) challenge of WT mice increased DARC expression in alveolar airway epithelial cells and that HDM challenge of WT and DARC ΔE2 mice induced a comparable pulmonary cellular infiltrate and immune phenotype (Th1 Th2 and Th17 associated cytokines). The only notable differences between WT and DARC ΔE2 mice were increased pulmonary neutrophils in DARC ΔE2 mice suggesting that DARC contributes to the resolution of neutrophil leak information.…”

“…75 Another molecule recently linked with the exacerbation of the allergic pulmonary inflammation and the asthma phenotype is the Duffy antigen receptor for chemokines (DARC). 77 DARC is membrane-bound atypical promiscuous chemokine receptor that binds immunomodulatory ligands including CXC and CC chemokines and cytokines. 78 DARC is thought to act as chemokine Rheostat as it lacks the characteristic Asp-Arg-Tyr (DRY) motif within the second cytoplasmic loop characteristic of G-protein coupled receptors and therefore lacks classical GPCR signalling.…”