Allosteric inhibition of CXCR1/2 by an orally bioavailable chemokine receptor inhibitor attenuates allergic lung inflammation in mice

摘要: MethodsNaïve C57BL/6 mice were sensitized with multiple intranasal doses of cat dander extract (CDE), then challenged with intranasal phosphate buffered saline (PBS) or CDE with or without administration of oral ladarixin via gavage. Allergic lung inflammation was assessed.ResultsCDE-challenge in sensitized mice induced allergic lung inflammation characterized by an increase in the number of BAL and lung neutrophils, eosinophils, RorγT positive cells, macrophages and dendritic cells that produced Il23, upregulation of mRNA expression of Cxcr2, Il4, Il5, IL13, IL6, IL1β, Tgfβ1, IL17, and IL23 in BAL cells, and an increase in the levels of serum total IgE and CDE specific IgE. Oral administration of ladarixin inhibited these parameters of Th2/Th17-associated allergic lung inflammation.ConclusionsThese observations indicate that allosteric inhibition of CXCR1/2 by an orally bioavailable chemokine receptor …