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.

中文翻译：

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ADAM10 通过抑制特定的骨髓细胞群来部分保护小鼠免受流感肺炎

流感病毒感染对全世界构成严重的健康威胁。骨髓细胞在调节先天性和适应性免疫防御方面发挥着关键作用。去整合素和金属蛋白酶 (ADAM) 蛋白质家族有助于各种免疫反应；然而，ADAM10 在流感病毒感染中的作用仍然很大程度上未知。在此，我们研究了其在小鼠流感病毒感染过程中的作用，重点是骨髓细胞。Adam10 ^flox/flox /Lyz2-Cre (Adam10 ^ΔLyz2 ) 和对照 Adam10 ^flox/flox小鼠鼻内感染了 200 个空斑形成单位的流感病毒 A/H1N1/PR8/34。亚当10 ^ΔLyz2与对照小鼠相比，小鼠表现出明显更高的死亡率、更强的肺部炎症和更高的肺部病毒滴度。感染后来自 Adam10 ^ΔLyz2小鼠的支气管肺泡灌洗液中的巨噬细胞和炎性细胞因子如 TNF-α、IL-1b 和 CCL2 增加。CD11b ⁺ Ly6G ^- F4/80 ⁺骨髓细胞具有炎症性单核细胞/巨噬细胞样表型，在 Adam10 ^ΔLyz2小鼠的肺中显着增加。过继转移实验表明，这些细胞可能导致 Adam10 ^ΔLyz2小鼠的预后较差。感染后 7 天，CD11b ⁺ Ly6G ^- F4/80 ⁺肺细胞在 Adam10 ^ΔLyz2小鼠中表现出显着高于对照小鼠的精氨酸酶 1 表达水平，而精氨酸酶 1 抑制剂改善了 Adam10 ^ΔLyz2小鼠的预后。增强的粒细胞-巨噬细胞集落刺激因子 (GM-CSF)/GM-CSF 受体信号可能促成了这一过程。总的来说，这些结果表明髓系 ADAM10 可以预防流感病毒肺炎，可能是一个有希望的治疗靶点。