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

Date Published: August 9, 2016

Publisher: Public Library of Science

Author(s): Victoria A. Meliopoulos, Lee-Ann Van de Velde, Nicholas C. Van de Velde, Erik A. Karlsson, Geoff Neale, Peter Vogel, Cliff Guy, Shalini Sharma, Susu Duan, Sherri L. Surman, Bart G. Jones, Michael D. L. Johnson, Catharine Bosio, Lisa Jolly, R. Gisli Jenkins, Julia L. Hurwitz, Jason W. Rosch, Dean Sheppard, Paul G. Thomas, Peter J. Murray, Stacey Schultz-Cherry, Sabra L. Klein.


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.

Partial Text

At each breath, the lung is challenged by a large number and diversity of microbes and other foreign material such as pollen and dust. Many inhaled microbes cause lethal infections if not contained by the lung immune system, which has evolved to balance rapid and efficient microbial clearance with protection of the delicate lung structure from excessive damage. Lung damage caused by microbial pathogens is the cause of acute lung injury (ALI), which leads to increased edema, alveolar permeability, and impaired oxygen exchange. In severe cases, ALI can result in impaired gas exchange function and ultimately death (acute respiratory distress syndrome or ARDS) [1]. To mitigate lung damage after infection, inflammation resolves, returning to homeostasis that restores normal lung function [2,3]. The air-interface structure of the lung involves a complex immune cell population including resident interstitial macrophages and dendritic cells, and GM-CSF-dependent alveolar macrophages [4–7]. A key question in understanding pulmonary immunity concerns how the balance between effective immune surveillance and maintenance of lung anatomy and physiology is achieved through life.

We propose a model where during pulmonary homeostasis, β6 integrin, possibly by activation of endogenous TGF-β1, suppresses CD11b expression on alveolar macrophages and type I IFN signaling within the lung microenvironment. However, in the absence of β6 integrin, CD11b expression is increased as is type I IFN signaling inducing a ‘primed’ antiviral state in the absence of infection (Fig 10). Through the use of TGF-β1 ‘rescue’ experiments and β6 KO mice lacking type I IFN signaling, we were able to demonstrate the resistance of β6 KO mice to influenza depended on the loss of TGF-β1 and this elevated type I IFN signaling, while the phenotypic changes in lung macrophages were independent of the type I IFN pathway at least at the level of type I IFN signaling as shown in the β6/IFNAR double KO mice.




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