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.