Introduction:
Asthma is a chronic inflammatory disease of the airways characterized by chronic eosinophilic and neutrophilic allergic inflammation. IL4-, IL5-, and IL13-producing CD4 T helper 2 (Th2)-cells1 and IL17-producing Th17 cells2,3contribute to this inflammation. IL4 stimulates Th2 differentiation of CD4+ T-cells by upregulating its master regulator GATA34, and these Th2-cells induce allergic lung inflammation4,5. IL23, IL1β, and IL6 stimulate CD4+ T-cells to differentiate toward Th176-8 by upregulating its master regulator retinoic acid–related orphan receptor- gamma t (RORγt)9, Th17 cells mediate neutrophilic inflammation10.
A large volume of literature indicates that CC-chemokine receptors (CCR) are present on eosinophils, Th2-cells, and Th17-cells, and modulate eosinophilic and neutrophilic airway inflammation in asthma by attenuating chemokine-induced migration and activation Th2-associated inflammatory immune cells11. CCR3 is expressed on eosinophils and regulates recruitment and degranulation of eosinophils12-14. CCR3, CCR4, and CCR8 are expressed on Th2-cells15, and CCR4 plays a role in recruiting Th2-cells16,17. CCR3 expressing eosinophils, and CCR4 and CCR8 expressing Th2-cells can be detected in endobronchial biopsies performed in asthmatic subjects after allergen challenge18. Th17-cells express CCR4, CCR5, and CCR619-23, and CCR6 facilitates recruitment of Th17-cells21,23.
Unlike the plethora of studies linking CCR receptors with allergic inflammation, less is known about the role of CXC-chemokine receptors (CXCR) in allergic inflammation. This is somewhat surprising because the levels of CXCL chemokines are elevated in the airways in asthma24-26, and the expression of CXCL1, CXCL5, and CXCL8 in bronchoalveolar lavage fluid (BALF) and endobronchial biopsies is higher in subjects with asthma than healthy control subjects2625. Furthermore, the levels of CXCL5 and CXCL8 are higher in patients with acute severe asthma24,25. CXCR1 and CXCR2 are G protein-coupled chemokine receptors for CXCL1, CXCL2, CXCL3, CXCL5, CXCL6, CXCL7, and CXCL8, and are expressed on many immune and lung structural cells27-29. We reported that administration of CXCR2 small molecule inhibitor SB225002 and dual CXCR1 and CXCR2 inhibitor reparixin suppressed allergic airway inflammation and serum IgE levels30,31. However, the role of CXCR1 and CXCR2 in modulating Th2 and Th17-associated allergic lung inflammation has not been reported.
Ladarixin is an orally bioavailable allosteric inhibitor of CXCR1 and CXCR2 that binds to an allosteric pocket of the trans-membrane region of both receptors with a 100-fold higher affinity than first-generation CXCR1 and CXCR2 inhibitors32. In the present study, we used ladarixin to examine the role of CXCR1 and CXCR2 in Th2 and Th17-associated allergic lung inflammation.