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Mint3/Apba3 depletion ameliorates severe murine influenza pneumonia and macrophage cytokine production in response to the influenza virus

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Schematic illustration showing the means by which Mint3 depletion attenuates inflammatory cytokine/chemokine production in IFV-infected macrophages.Mint3 depletion both activates AMPK and promotes IκBα accumulation in macrophages. These mechanisms contribute to inhibiting the nuclear translocation of NF-κB and the resulting inflammatory cytokine/chemokine production in IFV-infected macrophages.
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f6: Schematic illustration showing the means by which Mint3 depletion attenuates inflammatory cytokine/chemokine production in IFV-infected macrophages.Mint3 depletion both activates AMPK and promotes IκBα accumulation in macrophages. These mechanisms contribute to inhibiting the nuclear translocation of NF-κB and the resulting inflammatory cytokine/chemokine production in IFV-infected macrophages.

Mentions: In this study, we have shown that the Mint3-mediated pathway contributes to influenza pneumonia in mice. Mint3 depletion in mice reduced inflammatory cytokine/chemokine production and the infiltration of inflammatory cells in IFV-infected lungs, and improved mortality rates. In macrophages, Mint3 depletion also attenuated cytokine/chemokine production in response to IFV infection by suppressing the NF-κB signalling pathway. This suppression in Mint3−/− macrophages appeared to be mediated by two independent mechanisms: IκBα accumulation and AMPK activation (Fig. 6). Although how AMPK activation suppressed the NF-κB signalling pathway in Mint3−/− macrophages was unclear, several reported pathways such as SIRT1, PGCα1, and p53/FoxO might contribute to this suppression of the NF-κB signalling pathway by AMPK36.


Mint3/Apba3 depletion ameliorates severe murine influenza pneumonia and macrophage cytokine production in response to the influenza virus
Schematic illustration showing the means by which Mint3 depletion attenuates inflammatory cytokine/chemokine production in IFV-infected macrophages.Mint3 depletion both activates AMPK and promotes IκBα accumulation in macrophages. These mechanisms contribute to inhibiting the nuclear translocation of NF-κB and the resulting inflammatory cytokine/chemokine production in IFV-infected macrophages.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5121658&req=5

f6: Schematic illustration showing the means by which Mint3 depletion attenuates inflammatory cytokine/chemokine production in IFV-infected macrophages.Mint3 depletion both activates AMPK and promotes IκBα accumulation in macrophages. These mechanisms contribute to inhibiting the nuclear translocation of NF-κB and the resulting inflammatory cytokine/chemokine production in IFV-infected macrophages.
Mentions: In this study, we have shown that the Mint3-mediated pathway contributes to influenza pneumonia in mice. Mint3 depletion in mice reduced inflammatory cytokine/chemokine production and the infiltration of inflammatory cells in IFV-infected lungs, and improved mortality rates. In macrophages, Mint3 depletion also attenuated cytokine/chemokine production in response to IFV infection by suppressing the NF-κB signalling pathway. This suppression in Mint3−/− macrophages appeared to be mediated by two independent mechanisms: IκBα accumulation and AMPK activation (Fig. 6). Although how AMPK activation suppressed the NF-κB signalling pathway in Mint3−/− macrophages was unclear, several reported pathways such as SIRT1, PGCα1, and p53/FoxO might contribute to this suppression of the NF-κB signalling pathway by AMPK36.

View Article: PubMed Central - PubMed

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.

No MeSH data available.