Inhibition of CXCR1 and CXCR2 blocks allergen challenge-induced
Th17-associated mRNA expression and recruitment of Th17-cells
IL23 is a crucial cytokine that regulates the survival of Th17-cells and
mediates Th17
inflammation39-41.
Prior studies have shown that IL23, IL1β, and IL6 are elevated in the
BALF obtained from the subjects with asthma42,43and these cytokines stimulate Th17 differentiation6-8 by upregulating its
master regulator RORγt9. Building on our observation
that inhibiting CXCR1 and CXCR2 vigorously reduced the Th2-associated
mRNA expression levels and recruitment of Th2 cells, we examined the
effects of CDE challenge in sensitized mice (Fig 1A) on the
expression levels of IL23, IL1β, and IL6. CDE challenge upregulatedIl23, Il1b, and Il6 mRNA expression in BALF cells
(Fig 3A ) and lung tissues (Fig 3B ). CDE challenge
increased IL23 protein level in lung tissues (Fig 3C ), and the
numbers of IL23 positive T-cells, neutrophils, eosinophils, and lung
epithelial cells in single cells obtained from lung tissues (Fig
3D ). Oral administration of ladarixin blocked each of these effects of
CDE challenge (Fig 3A-D ).
Because inhibiting CXCR1 and CXCR2 reduced Th17-promoting cytokines, we
next evaluated the ability of CDE challenge in recruiting Th17-cells to
the lungs. Compared to naïve mice, CDE-challenge in CDE-SCM failed to
increase expression levels of Rorc mRNA (Fig 4A ). By
contrast, CDE challenge in CDE-MCM sensitized mice induced higher levels
of Rorc mRNA expression compared to naïve mice and mice subjected
to CDE-SCM (Fig 4A ). CDE challenge in CDE-MCM upregulatedIl17 and Rorc mRNA expression in BALF cells (Fig
4B ), upregulated Il17 mRNA in lung tissues (Fig 4C ),
increased the number of RORγt-expressing T-cells (Fig 4D ), and
IL17-expressing Th17-cells (Fig 4E ).
Oral administration of ladarixin
blocked each of these effects of CDE challenge (Fig 4B-E ),
including a remarkable 90% suppression of Il17 mRNA expression
(Fig 4B ).