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The Protective Role of a Disintegrin and Metalloprotease (ADAM) 10 During Severe Influenza Virus Infection
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A3841 - The Protective Role of a Disintegrin and Metalloprotease (ADAM) 10 During Severe Influenza Virus Infection
Author Block: S. Okamori1, M. Ishii1, T. Asakura1, S. Suzuki1, T. Kusumoto1, H. Kamata1, H. Namkoong1, K. Yagi1, S. Kagawa1, K. Horiuchi2, A. E. Hegab1, N. Hasegawa3, T. Betsuyaku1; 1Devision of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan, 2Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan, 3Center for Infectious Diseases and Infection Control, Keio University School of Medicine, Tokyo, Japan.
BACKGROUND: A disintegrin and metalloprotease (ADAM) 10, a transmembrane protein, contributes to the pathogenesis of lung inflammation via the cleavage of the extracellular domain of other membrane-bound proteins, such as cytokines, growth factors, receptors, and adhesion molecules. However, the relationship between ADAM10 and clinical diseases has not been elucidated. We previously reported that the survival rate following influenza A virus infection was significantly lower in Adam10flox/flox LysM-Cre+ (Adam10 conditional knockout [Adam10 cKO]) mice lacking the expression of ADAM10 in their myeloid cells than in control (Adam10flox/flox LysM-Cre-) mice. OBJECTIVES: We aimed to clarify the mechanism of the protective role of myeloid ADAM10 during murine influenza A virus infection. METHODS: Adam10 cKO and control mice were intranasally infected with 2 × 102 plaque-forming units (PFUs) of influenza A virus (PR8/H1N1). At day 1, 4, and 7 days after the intranasal infection, mice (n=6-8 in each group) were sacrificed and lungs were digested into single cell suspension. Lung cells were examined by flow cytometry for variation in myeloid cells. RESULTS: CD11b+F4/80+ macrophages were significantly increased in the lungs of Adam10 cKO mice compared to that in the lungs of the control mice. RT-PCR revealed remarkably higher expression of the arginase 1 mRNA in the lung CD11b+F4/80+ macrophages of Adam10 cKO mice. The arginase 1 protein expression in these cells was confirmed with immunofluorescent staining of the lung tissue. Treatment with a selective arginase inhibitor, Nω-hydroxy-nor-L-arginine, improved the survival rate of Adam10 cKO mice following influenza virus infection. CONCLUSION: Our results indicate that the protective role of myeloid ADAM10 during severe influenza virus infection may partially depend on suppression of arginase 1 expression in the lung CD11b+F4/80+ macrophages.
Author Block: S. Okamori1, M. Ishii1, T. Asakura1, S. Suzuki1, T. Kusumoto1, H. Kamata1, H. Namkoong1, K. Yagi1, S. Kagawa1, K. Horiuchi2, A. E. Hegab1, N. Hasegawa3, T. Betsuyaku1; 1Devision of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, Tokyo, Japan, 2Department of Orthopedic Surgery, Keio University School of Medicine, Tokyo, Japan, 3Center for Infectious Diseases and Infection Control, Keio University School of Medicine, Tokyo, Japan.
BACKGROUND: A disintegrin and metalloprotease (ADAM) 10, a transmembrane protein, contributes to the pathogenesis of lung inflammation via the cleavage of the extracellular domain of other membrane-bound proteins, such as cytokines, growth factors, receptors, and adhesion molecules. However, the relationship between ADAM10 and clinical diseases has not been elucidated. We previously reported that the survival rate following influenza A virus infection was significantly lower in Adam10flox/flox LysM-Cre+ (Adam10 conditional knockout [Adam10 cKO]) mice lacking the expression of ADAM10 in their myeloid cells than in control (Adam10flox/flox LysM-Cre-) mice. OBJECTIVES: We aimed to clarify the mechanism of the protective role of myeloid ADAM10 during murine influenza A virus infection. METHODS: Adam10 cKO and control mice were intranasally infected with 2 × 102 plaque-forming units (PFUs) of influenza A virus (PR8/H1N1). At day 1, 4, and 7 days after the intranasal infection, mice (n=6-8 in each group) were sacrificed and lungs were digested into single cell suspension. Lung cells were examined by flow cytometry for variation in myeloid cells. RESULTS: CD11b+F4/80+ macrophages were significantly increased in the lungs of Adam10 cKO mice compared to that in the lungs of the control mice. RT-PCR revealed remarkably higher expression of the arginase 1 mRNA in the lung CD11b+F4/80+ macrophages of Adam10 cKO mice. The arginase 1 protein expression in these cells was confirmed with immunofluorescent staining of the lung tissue. Treatment with a selective arginase inhibitor, Nω-hydroxy-nor-L-arginine, improved the survival rate of Adam10 cKO mice following influenza virus infection. CONCLUSION: Our results indicate that the protective role of myeloid ADAM10 during severe influenza virus infection may partially depend on suppression of arginase 1 expression in the lung CD11b+F4/80+ macrophages.
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