Respiratory Syncytial virus infection compromises asthma tolerance by recruiting interleukin-17A-producing cells via CCR6-CCL20 signaling

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HIGHLIGHTSAsthma and oral tolerance mouse models were established.RSV infection in tolerized mice incited asthma-like inflammatory responses.IL-17A producing cells were increased in the lungs and hilar LN and reduced in mesenteric LN in RSV-infected tolerized mice.Blockade of CCL20 reduced presentation of CCR6+ cells in RSV-infected tolerized HLN.Neutralization of IL-17A mitigated RSV infection-induced proinflammatory responses on asthma tolerance.Asthma tolerance can be induced by breast-feeding or oral feeding with ovalbumin (OVA). Anergy or deletion of specific T cells and generation of T regulatory cells might contribute to this process. However, whether respiratory syncytial virus (RSV) infection would affect asthma tolerance is not very clear. Here, we first established asthma and oral tolerance mouse models and then analyzed airway hypersensitivity and asthma-related genes in the lung, CCR6-expressing IL-17A+ cells in the lungs, hilar or mesenteric lymph nodes (HLN or MLN) among control, asthmatic, tolerized, RSV infection, and RSV-infected asthmatic and tolerized groups. We also administrated CCL20 or IL-17A neutralizing antibody to RSV-infected tolerized mice to test whether RSV infection would mobilize CCR6-expressing IL-17A+ cells from MLN to the infected lungs. We found that tolerized mice infected with RSV developed asthma-like responses manifested by increasing airway hypersensitivity, exacerbating peribronchial inflammation, elevating lung asthma-related genes (Il17a, Mu5ac, and Gob5), accumulating CCR6-expressing IL-17A+ cells in the lungs and HLN with a reduction of this cell population in MLN. CCL20-CCR6 co-expression in RSV-infected tolerized MLN was reduced. Neutralization of CCL20 reduced CD3+CD4+CCR6+ cells in the RSV-infected tolerized HLN. Neutralization of IL-17A mitigated the compromising effects of RSV infection on asthma tolerance. Taken together, RSV infection impairs asthma tolerance by recruiting IL-17A-producing cells via CCR6-CCL20 signaling. The findings provide novel insight into exacerbation and therapeutic strategy of asthma under RSV infection.

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