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An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens

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  • An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens

    PLoS Pathog. 2016 Aug 9;12(8):e1005804. doi: 10.1371/journal.ppat.1005804. eCollection 2016.
    An Epithelial Integrin Regulates the Amplitude of Protective Lung Interferon Responses against Multiple Respiratory Pathogens.

    Meliopoulos VA1, Van de Velde LA1,2, Van de Velde NC1,2, Karlsson EA1, Neale G3, Vogel P4, Guy C2, Sharma S2, Duan S2, Surman SL1, Jones BG1, Johnson MD1, Bosio C5, Jolly L6, Jenkins RG6, Hurwitz JL1, Rosch JW1, Sheppard D7, Thomas PG2, Murray PJ1,2, Schultz-Cherry S1.
    Author information

    Abstract

    The healthy lung maintains a steady state of immune readiness to rapidly respond to injury from invaders. Integrins are important for setting the parameters of this resting state, particularly the epithelial-restricted αVβ6 integrin, which is upregulated during injury. Once expressed, αVβ6 moderates acute lung injury (ALI) through as yet undefined molecular mechanisms. We show that the upregulation of β6 during influenza infection is involved in disease pathogenesis. β6-deficient mice (β6 KO) have increased survival during influenza infection likely due to the limited viral spread into the alveolar spaces leading to reduced ALI. Although the β6 KO have morphologically normal lungs, they harbor constitutively activated lung CD11b+ alveolar macrophages (AM) and elevated type I IFN signaling activity, which we traced to the loss of β6-activated transforming growth factor-β (TGF-β). Administration of exogenous TGF-β to β6 KO mice leads to reduced numbers of CD11b+ AMs, decreased type I IFN signaling activity and loss of the protective phenotype during influenza infection. Protection extended to other respiratory pathogens such as Sendai virus and bacterial pneumonia. Our studies demonstrate that the loss of one epithelial protein, αVβ6 integrin, can alter the lung microenvironment during both homeostasis and respiratory infection leading to reduced lung injury and improved survival.


    PMID: 27505057 DOI: 10.1371/journal.ppat.1005804
    [PubMed - as supplied by publisher]
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