Chronic spontaneous urticaria (CSU) lesions are characterized by infiltrates of eosinophils and basophils. Studies have suggested a role for the PGD2/CRTh2 and eotaxin/CCR3 pathways in eosinophil recruitment to CSU lesions. Eosinophils produce PGD2 in response to eotaxin, however the effects of PGD2 on CCR3 expression have not been examined. Therefore, we explored CCR3 and CRTh2 as shared recruitment/activation pathways for eosinophils and basophils.
We recruited adult CSU subjects (n=22) and non-allergic controls (n=8). Whole blood was analyzed for baseline CCR3 and CRTh2 expression on basophils and eosinophils by flow cytometry. CCR3 expression was examined in samples stimulated with PGD2 in the presence or absence of a CRTh2 antagonist (AZD1981).
Basophils from CSU subjects exhibited lower CRTh2 and CCR3 at baseline compared to healthy controls (p=0.0277 and p=0.0001). Eosinophil CRTh2 expression was also significantly lower in CSU subjects compared to controls (p=0.0049). CRTh2 and CCR3 were positively correlated on basophils (p=0.0157) and eosinophils (p=0.0036). Increasing concentrations of PGD2 reduced eosinophil CCR3 expression to a lesser extent in CSU subjects compared to controls (AUC 521.7 vs 624.6, p<0.0001). AZD1981 inhibited reductions in eosinophil CCR3 induced by PGD2 (10-6.5 M) in CSU subjects (p=0.0001) and healthy subjects (p=0.0469).
Reductions in basophil and eosinophil CRTh2 and CCR3 surface expression were positively correlated in CSU subjects. PGD2 exposure reduced eosinophil CCR3 expression in CSU and healthy subjects which was partially inhibited by CRTh2 antagonism. Further studies examining the coordination of these pathways may provide insights into the observed clinical benefits of CRTh2-targeting in eosinophilic subgroups.