Am J Physiol Lung Cell Mol Physiol . ADAM10 Partially Protects Mice against Influenza Pneumonia by Suppressing Specific Myeloid Cell Population

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Am J Physiol Lung Cell Mol Physiol


. 2021 Sep 15.
doi: 10.1152/ajplung.00619.2020. Online ahead of print.
ADAM10 Partially Protects Mice against Influenza Pneumonia by Suppressing Specific Myeloid Cell Population


Satoshi Okamori ^{1 2} , Makoto Ishii ¹ , Takanori Asakura ¹ , Shoji Suzuki ¹ , Ho Namkoong ¹ , Shizuko Kagawa ¹ , Ahmed E Hegab ¹ , Kazuma Yagi ¹ , Hirofumi Kamata ¹ , Tatsuya Kusumoto ¹ , Takunori Ogawa ¹ , Hayato Takahashi ³ , Masaki Yoda ⁴ , Keisuke Horiuchi ^{4 5} , Naoki Hasegawa ⁶ , Koichi Fukunaga ¹



Affiliations

• PMID: 34523355
• DOI: 10.1152/ajplung.00619.2020

Abstract

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contribute to various immune responses; however, the role of ADAM10 in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. Adam10^flox/flox/Lyz2-Cre (Adam10^ΔLyz2) and control Adam10^flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10^ΔLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines such as TNF-α, IL-1b, and CCL2 were increased in bronchoalveolar lavage fluid from Adam10^ΔLyz2 mice following infection. CD11b⁺Ly6G^-F4/80⁺ myeloid cells, which had an inflammatory monocytes/macrophages-like phenotype, were significantly increased in the lungs of Adam10^ΔLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10^ΔLyz2 mice. Seven days after infection, CD11b⁺Ly6G^-F4/80⁺ lung cells exhibited significantly higher arginase-1 expression levels in Adam10^ΔLyz2 mice than in control mice, while an arginase-1 inhibitor improved the prognosis of Adam10^ΔLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.

Keywords: ADAM10; GM-CSF; inflammatory monocytes; influenza.