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

doi:10.1016/j.isci.2021.103201

RSV infection-elicited high MMP-12-producing macrophages exacerbate allergic airway inflammation with neutrophil infiltration

iScience. 2021 Oct 2;24(10):103201. doi: 10.1016/j.isci.2021.103201. eCollection 2021 Oct 22.

Authors

Airi Makino^{1

2

3}, Takehiko Shibata^{1

2

3}, Mashiro Nagayasu^{2

3}, Ikuo Hosoya⁴, Toshiyo Nishimura⁵, Chihiro Nakano⁶, Kisaburo Nagata³, Toshihiro Ito⁵, Yoshimasa Takahashi², Shigeki Nakamura¹

Affiliations

¹ Department of Microbiology, Tokyo Medical University, Tokyo 160-8402, Japan.
² Department of Immunology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
³ Department of Biomolecular Science, Faculty of Science, Toho University, Chiba 274-8510, Japan.
⁴ Graduate School of Health Care Science, Bunkyo Gakuin University, Tokyo 113-8668, Japan.
⁵ Department of Immunology, Nara Medical University, Kashihara, Nara 634-8521, Japan.
⁶ Division of Respiratory Medicine, Department of Internal Medicine, Toho University Ohashi Medical Center, Tokyo 153-0044, Japan.

Abstract

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.

Keywords: Cell biology; Immunology; Pathophysiology; Virology.