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.

Abstract

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.

• Authors: Leon A Sokulsky, Keilah Garcia-Netto, Thi Hiep Nguyen, Jason L N Girkin, Adam Collison, Joerg Mattes, Gerard Kaiko, Chi Liu, Nathan W Bartlett, Ming Yang, Paul S Foster
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 205 Issue 9 Pg. 2468-2478 (11 01 2020) ISSN: 1550-6606 [Electronic] United States
• PMID: 32948685 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 by The American Association of Immunologists, Inc.

Chemical References

• Chemokine CXCL5
• Chemokines, CXC
• Cxcl3 protein, mouse
• Cxcl5 protein, mouse
• Cxcr2 protein, mouse
• Receptors, Interleukin-8B

Topics

• 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)