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.