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.