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.

Dual role of the miR‐146 family in rhinovirus‐induced airway inflammation and allergic asthma exacerbation

“…RV infection and replication in epithelial cells activate innate immune responses and induce expression of growth factors and chemokines, which leads to recruitment and activation of granulocytes, including neutrophils, destruction of normal airway tissue, and development of respiratory symptoms. 13,15,16 MicroRNAs (miRNAs) are short non-coding RNAs that modulate various biological processes through posttranscriptional regulation of gene expression. 17 More specifically, miRNAs recognize and bind to the 3′ untranslated regions (3′UTRs) of multiple target mRNAs via the complementarity of 6-to 8-nt-long seed regions present in miR-NAs.…”

“…From the minor group, RV‐A1b has often been used in research. RV infection and replication in epithelial cells activate innate immune responses and induce expression of growth factors and chemokines, which leads to recruitment and activation of granulocytes, including neutrophils, destruction of normal airway tissue, and development of respiratory symptoms 13,15,16 …”

NOX2-Deficient Neutrophils Facilitate Joint Inflammation Through Higher Pro-Inflammatory and Weakened Immune Checkpoint Activities

“…Neutrophils require Cxcl2 for more neutrophils recruitment ( 41 ). Inhibition of Cxcl3 in a mouse model of RV-induced exacerbation of asthma decreased the accumulation of Cxcr2 + neutrophils ( 42 ). Cxcl10-Cxcr3 acts in an autocrine way on the oxidative burst and chemotaxis in the inflamed neutrophils ( 43 ).…”

Indoleamine 2,3-Dioxygenase in Hematopoietic Stem Cell-Derived Cells Suppresses Rhinovirus-Induced Neutrophilic Airway Inflammation by Regulating Th1- and Th17-Type Responses

“…As the common cold virus, hRV is the most prevalent pathogen to circulate constantly in the human community, and it is known to be the most important trigger of asthma exacerbations ( 3 4 5 6 ). Even though murine models infected with minor or major groups of hRV have been used to depict several mechanisms that could explain asthma exacerbations ( 39 57 58 ), a better understanding of personal and environmental risk factors and inflammatory mechanisms is needed to develop new strategies that can prevent and treat asthma exacerbations. In this study, we have demonstrated that IDO is required to prevent neutrophilic airway inflammation during asthma exacerbations caused by hRV infection.…”