CXCR2 is required for neutrophilic airway inflammation and hyperresponsiveness in a mouse model of human rhinovirus infection.
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-alpha, MIP-2/CXCL2, and KC/CXCL1 and lower expression of MUC5B compared with RV-treated wild-type mice. The requirement of TNF-alpha 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-alpha release is required for airway hyperresponsiveness.
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI 48109-5688, USA.
Deepti R
DR
Nagarkar
Qiong
Q
Wang
Jee
J
Shim
Ying
Y
Zhao
Wan C
WC
Tsai
Nicholas W
NW
Lukacs
Uma
U
Sajjan
Marc B
MB
Hershenson
D000818:Animals; D001249:Asthma / Q000503:physiopathology*; D016535:Bronchial Hyperreactivity / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D054360:Chemokine CXCL1 / Q000276:immunology / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055257:Mucin-5B / Q000276:immunology / Q000378:metabolism; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000821:virology; D010850:Picornaviridae Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D012367:RNA, Viral / Q000032:analysis; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D012229:Rhinovirus; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; C524579:Muc5b protein, mouse; D055257:Mucin-5B; D012367:RNA, Viral; D023063:Receptors, Interleukin-8B; D047888:Receptors, Tumor Necrosis Factor, Type I; C506236:Tnfrsf1a protein, mouse; D014409:Tumor Necrosis Factor-alpha