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CXCR2 Is Required for Neutrophilic Airway Inflammation and Hyperresponsiveness in a Mouse Model of Human Rhinovirus Infection¹

Deepti R. Nagarkar,^* Qiong Wang,^* Jee Shim, Ying Zhao, Wan C. Tsai, Nicholas W. Lukacs, Uma Sajjan, and Marc B. Hershenson^2*

*Department of Molecular and Integrative Physiology, Department of Pediatrics and Communicable Diseases, and Department of Pathology, University of Michigan, Ann Arbor, MI 48109

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 with wild-type mice. Similar results were obtained in mice treated with neutralizing Ab to Ly6G, a neutrophil-depleting Ab. Lungs from RV-infected, CXCR2^–/– mice showed significantly reduced production of TNF-, MIP-2/CXCL2, and KC/CXCL1 and lower expression of MUC5B compared with RV-treated wild-type mice. The requirement of TNF- for RV1B-induced airway responses was tested using TNFR1^–/– mice. TNFR1^–/– animals displayed reduced airway 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- release is required for airway hyperresponsiveness.

² Address correspondence and reprint requests to Dr. Marc B. Hershenson, University of Michigan, 1150 West Medical Center Drive, Room 3570 MSRBII, Box 5688, Ann Arbor, MI 48109-5688. E-mail address: mhershen{at}umich.edu

¹ This work was supported by National Institutes of Health Grants HL082550 and HL081420 (to M.B.H.).