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.
Highlights
Munc18–1-interacting protein 3 (Mint3), known as amyloid-βA4 precursor protein-binding family A member 3 (Apba3), is a member of the X11 protein family[20,21]
Given that inflammatory cytokines/chemokines are linked to lung damage in severe influenza pneumonia[12,13,14,17,18,19,30], we analysed the infiltrated cells and cytokine/chemokine levels in bronchoalveolar lavage fluid (BALF) collected from the influenza virus (IFV)-infected lungs of WT and Mint3−/− mice
We have shown that the Mint3-mediated pathway contributes to influenza pneumonia in mice
Summary
Munc18–1-interacting protein 3 (Mint3), known as amyloid-βA4 precursor protein-binding family A member 3 (Apba3), is a member of the X11 protein family[20,21]. Mint3-deficient macrophages showed impaired cytokine production in response to lipopolysaccharide (LPS)[27]. Since FIH-1 hydroxylates molecules other than HIF-1αincluding IκBα29 which inhibits the NF-κB signalling, FIH-1 suppression by Mint[3] might affect inflammatory cytokine/ chemokine production via HIF-1 and the NFκB signalling in macrophages. Because macrophages are one of the main sources of inflammatory cytokines/chemokines, here we hypothesized that Mint[3] likely played roles in influenza pneumonia and in host protection against IFV. Our results showed that Mint[3] depletion in mice attenuated fatal influenza pneumonia through the reduction of inflammatory cytokine/ chemokine production and neutrophil infiltration without affecting type-I interferon production and anti-viral acquired immunity. Mint[3] inhibition might represent one of the likely targets for the treatment of severe influenza pneumonia
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