RSV infection-elicited high MMP-12–producing macrophages exacerbate allergic airway inflammation with neutrophil infiltration
Airi Makino,
Takehiko Shibata,
Mashiro Nagayasu,
Ikuo Hosoya,
Toshiyo Nishimura,
Chihiro Nakano,
Kisaburo Nagata,
Toshihiro Ito,
Yoshimasa Takahashi,
Shigeki Nakamura
Affiliations
Airi Makino
Department of Microbiology, Tokyo Medical University, Tokyo 160-8402, Japan; Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Biomolecular Science, Faculty of Science, Toho University, Chiba 274-8510, Japan
Takehiko Shibata
Department of Microbiology, Tokyo Medical University, Tokyo 160-8402, Japan; Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Biomolecular Science, Faculty of Science, Toho University, Chiba 274-8510, Japan; Corresponding author
Mashiro Nagayasu
Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Biomolecular Science, Faculty of Science, Toho University, Chiba 274-8510, Japan
Ikuo Hosoya
Graduate School of Health Care Science, Bunkyo Gakuin University, Tokyo 113-8668, Japan
Toshiyo Nishimura
Department of Immunology, Nara Medical University, Kashihara, Nara 634-8521, Japan
Chihiro Nakano
Division of Respiratory Medicine, Department of Internal Medicine, Toho University Ohashi Medical Center, Tokyo 153-0044, Japan
Kisaburo Nagata
Department of Biomolecular Science, Faculty of Science, Toho University, Chiba 274-8510, Japan
Toshihiro Ito
Department of Immunology, Nara Medical University, Kashihara, Nara 634-8521, Japan
Yoshimasa Takahashi
Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
Shigeki Nakamura
Department of Microbiology, Tokyo Medical University, Tokyo 160-8402, Japan
Summary: Respiratory syncytial virus (RSV) infection often exacerbates bronchial asthma, but there is no licensed RSV vaccine or specific treatments. Here we show that RSV-induced alveolar macrophages, which produce high levels of matrix metalloproteinase-12 (MMP-12), exacerbate allergic airway inflammation with increased neutrophil infiltration. When mice subjected to allergic airway inflammation via exposure to the house dust mite antigen (HDM) were infected with RSV (HDM/RSV), MMP-12 expression, viral load, neutrophil infiltration, and airway hyperresponsiveness (AHR) were increased compared to those in the HDM and RSV groups. These exacerbations in the HDM/RSV group were attenuated in MMP-12-deficient mice and mice treated with MMP408, a selective MMP-12 inhibitor, but not in mice treated with dexamethasone. Finally, M2-like macrophages produced MMP-12, and its production was promoted by increase of IFN-β-induced IL-4 receptor expression with RSV infection. Thus, targeting MMP-12 represents a potentially novel therapeutic strategy for the exacerbation of asthma.
