ADAM10 partially protects mice against influenza pneumonia by suppressing specific myeloid cell population

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 contributes to various immune responses; however, the role of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. ADAM10 gene (Adam10)^flox/fl^ox/Lyz2-Cre (Adam10^DLyz2) and control Adam10^flox/fl^ox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10^DLyz2 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-a, IL-1b, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10^DLyz2 mice following infection. CD11b⁺Ly6G^-F4/80⁺ myeloid cells, which had an inflammatory monocyte/macrophage-like phenotype, were significantly increased in the lungs of Adam10^DLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10^DLyz2 mice. Seven days after infection, CD11b⁺Ly6G^-F4/80⁺ lung cells exhibited significantly higher arginase-1 expression levels in Adam10^DLyz2 mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10^DLyz2 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.