title: Mint3/Apba3 depletion ameliorates severe murine influenza pneumonia and macrophage cytokine production in response to the influenza virus.
abstract: Influenza virus (IFV) infection is a common cause of severe pneumonia. Studies have suggested that excessive activation of the host immune system including macrophages is responsible for the severe pathologies mediated by IFV infection. Here, we focused on the X11 protein family member Mint3/Apba3, known to promote ATP production via glycolysis by activating hypoxia inducible factor-1 (HIF-1) in macrophages, and examined its roles in lung pathogenesis and anti-viral defence upon IFV infection. Mint3-deficient mice exhibited improved influenza pneumonia with reduced inflammatory cytokines/chemokine levels and neutrophil infiltration in the IFV-infected lungs without alteration in viral burden, type-I interferon production, or acquired immunity. In macrophages, Mint3 depletion attenuated NF-κB signalling and the resultant cytokine/chemokine production in response to IFV infection by increasing IκBα and activating the cellular energy sensor AMPK, respectively. Thus, Mint3 might represent one of the likely therapeutic targets for the treatment of severe influenza pneumonia without affecting host anti-viral defence through suppressing macrophage cytokine/chemokine production.
authors.affiliation: Biomedical Laboratory, Department of Biomedical Research, Kitasato University Medical Center, Arai, Kitamoto, Saitama, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Uematsu
authors.affiliation: Biomedical Laboratory, Department of Biomedical Research, Kitasato University Medical Center, Arai, Kitamoto, Saitama, Japan.|Innovation Laboratory, NEC Solution Innovators, Ltd., Kashiwanoha, Kashiwa, Chiba, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
authors.forename: Hiroki J
authors.initials: HJ
authors.lastname: Nakaoka
authors.affiliation: Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.affiliation: Biomedical Laboratory, Department of Biomedical Research, Kitasato University Medical Center, Arai, Kitamoto, Saitama, Japan.
authors.forename: Noritada
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Murakami
authors.affiliation: Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Takara-machi, Kanazawa, Ishikawa, Japan.
authors.forename: Motoharu
authors.initials: M
authors.lastname: Seiki
authors.affiliation: Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, Shirokanedai, Minato-ku, Tokyo, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Sakamoto
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D006019:Glycolysis / Q000502:physiology; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000821:virology; D008264:Macrophages / Q000378:metabolism* / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D009975:Orthomyxoviridae / Q000472:pathogenicity; D009976:Orthomyxoviridae Infections / Q000378:metabolism* / Q000821:virology; D011014:Pneumonia / Q000378:metabolism* / Q000821:virology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C485530:Apba3 protein, mouse; D016207:Cytokines; D051793:Hypoxia-Inducible Factor 1; D016328:NF-kappa B; D000255:Adenosine Triphosphate