Background: IL-8 activates neutrophils through CXCR1. Elastase cleaves CXCR1, but the cellular machinery involved remains poorly understood. Results: Here we show that secretases and PAR-2 regulate elastase-mediated cleavage of CXCR1. Conclusion: These studies establish a novel network of elastase, secretases, and PAR-2 that regulates CXCR1 on neutrophils. Significance: Targeting this network may lead to novel therapeutic strategies in neutrophilic diseases, such as cystic fibrosis.