Inhibition of CXCR1 and CXCR2 blocks Th2/Th17-associated Allergic Lung Inflammation in Mice

Background: IL4, IL5, IL13, and IL17-producing CD4 T helper 2 (Th2)-cells and IL17-producing CD4 T helper 17 (Th17)-cells contribute to chronic eosinophilic and neutrophilic airway inflammation in asthma and allergic airway inflammation. Chemokines and their receptors are upregulated in Th2-Th17-mediated inflammation. However, the ability of CXCR1 and CXCR2 inhibition to suppress Th2 and Th17 cell-mediated allergic lung inflammation has not been reported. Methods: Mice sensitized and challenged with cat dander extract (CDE) mount a vigorous Th2-Th17-mediated allergic lung inflammation. Ladarixin is an orally bioavailable allosteric inhibitor of CXCR1 and CXCR2 and was orally administered in this model prior to CDE-challenge. The ability of ladarixin to modulate allergen-challenge induced recruitment of cytokine-secreting CXCR1 and CXCR2-expressing Th2- and Th17-cells and allergic lung inflammation were examined. Results: Allergen challenge in sensitized mice increased mRNA expression levels of Il4, Il5, Il13, Il6, Il1β, Tgfβ1, Il17, Il23, Gata3, and Rorc, recruited CXCR1- and CXCR2-expressing Th2 cells, Th17-cells, neutrophils, and eosinophils, inducing allergic lung inflammation. Administration of ladarixin vigorously blocked each of these pro-inflammatory effects of allergen challenge. Conclusions: Allosteric inhibition of CXCR1 and CXCR2 by oral administration of ladarixin vigorously blocks recruitment of CXCR1- and CXCR2-expressing Th2-cells, Th17-cells, neutrophils, and eosinophils in this mouse model of allergic lung inflammation. We suggest that the ability of oral ladarixin to mitigate Th2 and Th17-mediated allergic inflammation should be investigated in humans.