Abstract
BackgroundRespiratory viral infections are one of the leading causes of need for emergency care and hospitalizations in asthmatic individuals, and airway-secreted cytokines are released within hours of viral infection to initiate these exacerbations. IL-33, specifically, contributes to these allergic exacerbations by amplifying type 2 inflammation. We hypothesized that blocking IL-33 in RSV-induced exacerbation would significantly reduce allergic inflammation.MethodsSensitized BALB/c mice were challenged with aerosolized ovalbumin (OVA) to establish allergic inflammation, followed by RSV-A2 infection to yield four treatment groups: saline only (Saline), RSV-infected alone (RSV), OVA alone (OVA), and OVA-treated with RSV infection (OVA-RSV). Lung outcomes included lung mRNA and protein markers of allergic inflammation, histology for mucus cell metaplasia and lung immune cell influx by cytospin and flow cytometry.ResultsWhile thymic stromal lymphopoietin (TSLP) and IL-33 were detected 6 h after RSV infection in the OVA-RSV mice, IL-23 protein was uniquely upregulated in RSV-infected mice alone. OVA-RSV animals varied from RSV- or OVA-treated mice as they had increased lung eosinophils, neutrophils, group 2 innate lymphoid cells (ILC2) and group 3 innate lymphoid cells (ILC3) detectable as early as 6 h after RSV infection. Neutralized IL-33 significantly reduced ILC2 and eosinophils, and the prototypical allergic proteins, IL-5, IL-13, CCL17 and CCL22 in OVA-RSV mice. Numbers of neutrophils and ILC3 were also reduced with anti-IL-33 treatment in both RSV and OVA-RSV treated animals as well.ConclusionsTaken together, our findings indicate a broad reduction in allergic-proinflammatory events mediated by IL-33 neutralization in RSV-induced asthma exacerbation.
Highlights
Respiratory viral infections are one of the leading causes of need for emergency care and hospitalizations in asthmatic individuals, and airway-secreted cytokines are released within hours of viral infection to initiate these exacerbations
Several genes were upregulated in response to OVA sensitization and challenge in comparison to saline-treated animals including Ccl11, Ccl12, Ccl17, Ccl5, Ccr3, Cd40l, Cysltr1, Il13, Il13ra, Il33, Il4, Itga4, and Tslp
Those genes that had significantly (P < 0.05) higher expression in the OVA-RSV mice compared to the OVA mice included, Ccl17, Ccl22, Ccr4, Clca1, Crlf2 (TSLP receptor), Rnase2a, Gata3, Ptgdr2, Il33, Kit, Mmp9, Muc5ac, Rorc, Stat5a and Stat6 (Fig. 1C)
Summary
Respiratory viral infections are one of the leading causes of need for emergency care and hospitalizations in asthmatic individuals, and airway-secreted cytokines are released within hours of viral infection to initiate these exacerbations. IL-33, contributes to these allergic exacerbations by amplifying type 2 inflammation. We hypothesized that blocking IL-33 in RSV-induced exacerbation would significantly reduce allergic inflammation. Respiratory viral infections commonly exacerbate and, Warren et al Respir Res (2021) 22:206. (See figure on page.) Fig. 1 Biomarkers of allergic lung inflammation are augmented in allergic-OVA mice infected with RSV. A Mice were intranasally infected with purified RSV-A2 24 h following final OVA airway challenge. Four groups of mice were included in each experiment; saline-treated alone (Saline), RSV-infected (RSV), OVA-treated alone (OVA), and OVA-treated, RSV-infected (OVA-RSV). ANOVA was used to determine of statistical significance and Kruskal–Wallis post-test analysis was used to determine the statistical significance between groups. *Indicates P < 0.05
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