CXCR2 is required for neutrophilic airways inflammation and hyperresponsiveness in a mouse model of human rhinovirus infection

摘要

Human rhinovirus (RV) infection is responsible for the majority of virus-induced asthma exacerbations. Using a mouse model of human RV infection, we sought to determine the requirement of CXCR2, the receptor for ELR-positive CXC chemokines, for RV-induced airway neutrophilia and hyperresponsiveness. Wild-type and CXCR2 −/− mice were inoculated intranasally with RV1B or sham HeLa cell supernatant. Following RV1B infection, CXCR2 −/− mice showed reduced airway and lung neutrophils and cholinergic responsiveness compared to wild-type mice. Similar results were obtained in mice treated with neutralizing antibody to Ly6G, a neutrophil-depleting antibody. Lungs from RV-infected, CXCR2 −/− mice showed significantly reduced production of tumor necrosis factor (TNF)-α, MIP-2/CXCL2 and KC/CXCL1, and lower expression of MUC5B, compared to RV-treated wild-type mice. The requirement of TNF-α for RV1B-induced airways responses was tested using TNF receptor (TNFR)-1 −/− mice. TNFR1 −/− animals displayed reduced airways responsiveness to RV1B, even when exogenous MIP-2 was added to the airways. We conclude that CXCR2 is required for RV-induced neutrophilic airway inflammation, and that neutrophil TNF-α release is required for airways hyperresponsiveness.