Allosteric inhibition of CXCR1 and CXCR2 abrogates 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 modulate 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. Allosteric inhibitor of CXCR1 and CXCR2, ladarixin was orally administered in this model. The ability of ladarixin to modulate allergen-challenge induced recruitment of 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 and , and induced allergic lung inflammation characterized by recruitment of CXCR1- and CXCR2-expressing Th2-cells, Th17-cells, neutrophils, and eosinophils. Allosteric inhibition of CXCR1 and CXCR2 vigorously blocked each of these pro-inflammatory effects of allergen challenge. CXCL chemokines induced a CXCR1 and CXCR2-dependent proliferation of IL4, IL5, IL13, and IL17 expressing T-cells.

Conclusion: Allosteric inhibition of CXCR1 and CXCR2 abrogates 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 allosteric inhibition of CXCR1 and CXCR2 to abrogate Th2 and Th17-mediated allergic inflammation should be investigated in humans.