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/flox)/Lyz2-Cre (Adam10(Delta Lyz2)) and control Adam10(flox/flox) mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10(Delta Lyz2 )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-alpha, IL-1 beta, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10(Delta Lyz2) 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(Delta Lyz2) mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10(Delta Lyz2) mice. Seven days after infection, CD11b(+) Ly6G(-)F4/80(+) lung cells exhibited significantly higher arginase-1 expression levels in Adam10(Delta Lyz2) mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10(Delta Lyz2) 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.

Automated summary

The study showed that ADAM10 plays a protective role in regulating influenza virus infection and may be a potential therapeutic target.