A Critical Role for the CXCL3/CXCL5/CXCR2 Neutrophilic Chemotactic Axis in the Regulation of Type 2 Responses in a Model of Rhinoviral-Induced Asthma Exacerbation

Rhinovirus (RV) infections in asthmatic patients are often associated with asthma exacerbation, characterized by worsened airways hyperreactivity and increased immune cell infiltration to the airways. The C-X-C chemokines, CXCL3 and CXCL5, regulate neutrophil trafficking to the lung via CXCR2, and t...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2020-11, Vol.205 (9), p.2468-2478
Main Authors: Sokulsky, Leon A, Garcia-Netto, Keilah, Nguyen, Thi Hiep, Girkin, Jason L N, Collison, Adam, Mattes, Joerg, Kaiko, Gerard, Liu, Chi, Bartlett, Nathan W, Yang, Ming, Foster, Paul S
Format: Article
Language:English
Subjects:
Animals
Asthma - immunology
Bronchial Hyperreactivity - immunology
Chemokine CXCL5 - immunology
Chemokines, CXC - immunology
Chemotaxis, Leukocyte - immunology
Eosinophils - immunology
Immunity, Innate - immunology
Inflammation - immunology
Lung - immunology
Lymphocytes - immunology
Male
Mice
Mice, Inbred BALB C
Neutrophils - immunology
Receptors, Interleukin-8B - immunology
Rhinovirus - immunology
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Summary:Rhinovirus (RV) infections in asthmatic patients are often associated with asthma exacerbation, characterized by worsened airways hyperreactivity and increased immune cell infiltration to the airways. The C-X-C chemokines, CXCL3 and CXCL5, regulate neutrophil trafficking to the lung via CXCR2, and their expression in the asthmatic lung is associated with steroid-insensitive type 2 inflammatory signatures. Currently, the role of CXCL3 and CXCL5 in regulating neutrophilic and type 2 responses in viral-induced asthma exacerbation is unknown. Inhibition of CXCL3 or CXCL5 with silencing RNAs in a mouse model of RV-induced exacerbation of asthma attenuated the accumulation of CXCR2 neutrophils, eosinophils, and innate lymphoid cells in the lung and decreased production of type 2 regulatory factors IL-25, IL-33, IL-5, IL-13, CCL11, and CCL24. Suppression of inflammation was associated with decreased airways hyperreactivity, mucus hypersecretion, and collagen deposition. Similar results were obtained by employing RC-3095, which has been shown to bind to CXCR2, or by depletion of neutrophils. Our data demonstrate that CXCL3 and CXCL5 may be critical in the perpetuation of RV-induced exacerbation of asthma through the recruitment of CXCR2-positive neutrophils and by promoting type 2 inflammation. Targeting the CXCL3/CXCL5/CXCR2 axis may provide a new therapeutic approach to attenuating RV-induced exacerbations of asthma.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1901350