tetano
Editor, Senior Moderator
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[SUP] 1 2 [/SUP], Makoto Ishii[SUP] 1 [/SUP], Takanori Asakura[SUP] 1 [/SUP], Shoji Suzuki[SUP] 1 [/SUP], Ho Namkoong[SUP] 1 [/SUP], Shizuko Kagawa[SUP] 1 [/SUP], Ahmed E Hegab[SUP] 1 [/SUP], Kazuma Yagi[SUP] 1 [/SUP], Hirofumi Kamata[SUP] 1 [/SUP], Tatsuya Kusumoto[SUP] 1 [/SUP], Takunori Ogawa[SUP] 1 [/SUP], Hayato Takahashi[SUP] 3 [/SUP], Masaki Yoda[SUP] 4 [/SUP], Keisuke Horiuchi[SUP] 4 5 [/SUP], Naoki Hasegawa[SUP] 6 [/SUP], Koichi Fukunaga[SUP] 1 [/SUP]
Affiliations
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[SUP]flox/flox[/SUP]/Lyz2-Cre (Adam10[SUP]ΔLyz2[/SUP]) and control Adam10[SUP]flox/flox[/SUP] mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10[SUP]ΔLyz2[/SUP] 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[SUP]ΔLyz2[/SUP] mice following infection. CD11b[SUP]+[/SUP]Ly6G[SUP]-[/SUP]F4/80[SUP]+[/SUP] myeloid cells, which had an inflammatory monocytes/macrophages-like phenotype, were significantly increased in the lungs of Adam10[SUP]ΔLyz2[/SUP] mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10[SUP]ΔLyz2[/SUP] mice. Seven days after infection, CD11b[SUP]+[/SUP]Ly6G[SUP]-[/SUP]F4/80[SUP]+[/SUP] lung cells exhibited significantly higher arginase-1 expression levels in Adam10[SUP]ΔLyz2[/SUP] mice than in control mice, while an arginase-1 inhibitor improved the prognosis of Adam10[SUP]ΔLyz2[/SUP] 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.
. 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[SUP] 1 2 [/SUP], Makoto Ishii[SUP] 1 [/SUP], Takanori Asakura[SUP] 1 [/SUP], Shoji Suzuki[SUP] 1 [/SUP], Ho Namkoong[SUP] 1 [/SUP], Shizuko Kagawa[SUP] 1 [/SUP], Ahmed E Hegab[SUP] 1 [/SUP], Kazuma Yagi[SUP] 1 [/SUP], Hirofumi Kamata[SUP] 1 [/SUP], Tatsuya Kusumoto[SUP] 1 [/SUP], Takunori Ogawa[SUP] 1 [/SUP], Hayato Takahashi[SUP] 3 [/SUP], Masaki Yoda[SUP] 4 [/SUP], Keisuke Horiuchi[SUP] 4 5 [/SUP], Naoki Hasegawa[SUP] 6 [/SUP], Koichi Fukunaga[SUP] 1 [/SUP]
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[SUP]flox/flox[/SUP]/Lyz2-Cre (Adam10[SUP]ΔLyz2[/SUP]) and control Adam10[SUP]flox/flox[/SUP] mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10[SUP]ΔLyz2[/SUP] 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[SUP]ΔLyz2[/SUP] mice following infection. CD11b[SUP]+[/SUP]Ly6G[SUP]-[/SUP]F4/80[SUP]+[/SUP] myeloid cells, which had an inflammatory monocytes/macrophages-like phenotype, were significantly increased in the lungs of Adam10[SUP]ΔLyz2[/SUP] mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10[SUP]ΔLyz2[/SUP] mice. Seven days after infection, CD11b[SUP]+[/SUP]Ly6G[SUP]-[/SUP]F4/80[SUP]+[/SUP] lung cells exhibited significantly higher arginase-1 expression levels in Adam10[SUP]ΔLyz2[/SUP] mice than in control mice, while an arginase-1 inhibitor improved the prognosis of Adam10[SUP]ΔLyz2[/SUP] 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.