Effect of alternative CXCR2 ligands on human neutrophils in vitro

Targeting neutrophils has emerged as a promising therapeutic strategy for various inflammatory diseases. Here, we investigate a highly specific monoclonal antibody that targets CXCR2, which is a major chemokine receptor on neutrophils. This antibody functions as an inverse agonist, binds tightly to CXCR2 in a mutually exclusive manner versus IL-8, and completely blocks CXCR2-β-arrestin signaling and subsequent neutrophil functions. Treatment with the antibody appears to result in an overall reversal of IL-8 induced gene expressions in primary human neutrophils. The antibody demonstrates remarkable efficacy in controlling dysregulated neutrophil activity in peripheral circulation and inflammatory tissues in four inflammation animal models. In addition, administration of the antibody not only ameliorates the symptoms of neutrophilia, but also mitigates tissue damage in cases of acute lung inflammation and delayed-type-hypersensitivity reactions. We also checked the effects of the antibody on human neutrophils activated by the natural ligand IL-8 or not in vitro through RNAseq. We used human primary neutrophils to verify the functional gene expression differences in neutrophils with and without lps stimulation and/or abN48-2-IgG1 treatment.