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

PLoS Pathogens

Bart G. Jones¹  Geoff Neale¹  Stacey Schultz-Cherry¹  Susu Duan¹  Sherri L. Surman¹  Nicholas C. Van de Velde¹  Victoria A. Meliopoulos²  Lee-Ann Van de Velde²  Paul G. Thomas²  Michael D. L. Johnson²  Peter Vogel²  Lisa Jolly²  Catharine Bosio²  Dean Sheppard²  Erik A. Karlsson²  Peter J. Murray³  Shalini Sharma⁴  Julia L. Hurwitz⁵  Jason W. Rosch⁵  R. Gisli Jenkins⁶  Cliff Guy⁷ 

[1] Department of Immunology, St Jude Children’s Research Hospital, Memphis, Tennessee, United States of America;Department of Infectious Diseases, St Jude Children’s Research Hospital, Memphis, Tennessee, United States of America;Department of Medicine, Division of Pulmonary, Critical Care, Allergy, and Sleep Medicine, UCSF Medical Center, San Francisco, California, United States of America;Department of Veterinary Pathology Core, St Jude Children’s Research Hospital, Memphis, Tennessee, United States of America;Division of Respiratory Medicine, University of Nottingham, Nottingham, United Kingdom;Rocky Mountain Laboratories, NIAID, NIH, Hamilton, Montana, United States of America;The Hartwell Center, St Jude Children’s Research Hospital, Memphis, Tennessee, United States of America

关键词: Alveolar macrophages;    Respiratory infections;    Influenza;    Integrins;    Interferons;    Influenza viruses;    Macrophages;    Inflammation;   

DOI  :  10.1371/journal.ppat.1005804

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY