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