Inhibition of CXCR1 and CXCR2 blocks allergen challenge-induced
DNA damage and restores genome integrity
We have previously reported that allergen challenge including
CDE-challenge induces oxidative stress and DNA damage in the lung, and
damaged DNA contributes to allergic lung inflammation30,34,47-49.
Building on our observation that CXCR1 and CXCR2 are key regulators of
Th2 and Th17-mediated allergic inflammation, we hypothesized that
ladarixin may inhibit CDE challenge-induced lung DNA damage by
suppressing the recruitment of ROS-generating inflammatory cells. To
determine if treatment with ladarixin rescues CDE-mediated oxidative
genome damage, we performed gene-specific LA-qPCR and analyzed DNA
damage in two representative genes, pol β and β globin . In
the long amplicons of pol β and β-globin , there is a
higher probability of oxidative genome damage that can block the
elongating Taq DNA polymerase and consequently, there will be less
efficient PCR
amplification35,36.
In a short amplicon, the probability of genome damage is much lower and
comparable PCR amplification efficiency is expected. Compared to CDE
challenge in sensitized mice without ladarixin, oral treatment of
ladarixin along with and after CDE challenge in CDE-MCM reduced long
amplicon PCR product, indicating less DNA damage and restoration of
genome integrity (Fig 6A and B ). Together these data indicate
that ladarixin rescues mice from CDE challenge-induced lung DNA damage.