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

• DOI: 10.1371/journal.ppat.1005804
• Publication Date: 2016-08-09T17:40:58Z
• Authors: Victoria A. Melio...; Lee-Ann Van de Velde; Nicholas C. Van d...; Erik A. Karlsson; Geoff Neale; Peter Vogel; Cliff Guy; Shalini Sharma; Susu Duan; Sherri L. Surman; Bart G. Jones; Michael D. L. Joh...; Catharine Bosio; Lisa Jolly; R. Gisli Jenkins; Julia L. Hurwitz; Jason W. Rosch; Dean Sheppard; Paul G. Thomas; Peter J. Murray; Stacey Schultz-Ch...
• Keywords: Male; 0301 basic medicine; Integrins; QH301-705.5; Immunoblotting; Fluorescent Antibody Technique; Enzyme-Linked Immunosorbent Assay; Real-Time Polymerase Chain Reaction; Mice; 03 medical and health sciences; Antigens, Neoplasm; Macrophages, Alveolar; Animals; Biology (General); Lung; Respiratory Tract Infections; Oligonucleotide Array Sequence Analysis; Mice, Knockout; RC581-607; Flow Cytometry; Adoptive Transfer; 3. Good health; Mice, Inbred C57BL; Disease Models, Animal; Interferon Type I; Female; Immunologic diseases. Allergy; Research Article

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.