Timed Action of IL-27 Protects from Immunopathology while Preserving Defense in Influenza

PLoS Pathogens

Christopher A. Hunter¹  Ute Hoffmann¹  Jan M. Schwab²  Christiaan J. M. Saris³  Ralf Watzlawick⁴  Elisabeth E. Kenngott⁴  Alf Hamann⁴  Gudrun F. Debes⁴  Micha F. Schröter⁵  Thorsten Wolff⁵  Jason S. Stumhofer⁵  Francesca Diane M. Liu⁵  Anja Kühl⁵  Silke Jennrich⁶  Alexander Scheffold⁷  Stephen Norley⁷ 

[1] Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany;Department of Inflammation Research, Amgen Inc., Thousand Oaks, California, United States of America;Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America;Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America;Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin, Germany;Research Center ImmunoSciences (RCIS), Charité-Universitätsmedizin Berlin, Berlin, Germany;Robert Koch-Institut, Berlin, Germany

关键词: T cells;    Influenza viruses;    Influenza;    Immunopathology;    Neutrophils;    Inflammation;    Chemokines;    Cytokines;   

DOI  :  10.1371/journal.ppat.1004110

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Infection with influenza virus can result in massive pulmonary infiltration and potentially fatal immunopathology. Understanding the endogenous mechanisms that control immunopathology could provide a key to novel adjunct therapies for this disease. Here we show that the cytokine IL-27 plays a crucial role in protection from exaggerated inflammation during influenza virus infection. Using Il-27ra−/− mice, IL-27 was found to limit immunopathology, neutrophil accumulation, and dampened TH1 or TH17 responses via IL-10–dependent and -independent pathways. Accordingly, the absence of IL-27 signals resulted in a more severe disease course and in diminished survival without impacting viral loads. Consistent with the delayed expression of endogenous Il-27p28 during influenza, systemic treatment with recombinant IL-27 starting at the peak of virus load resulted in a major amelioration of lung pathology, strongly reduced leukocyte infiltration and improved survival without affecting viral clearance. In contrast, early application of IL-27 impaired virus clearance and worsened disease. These findings demonstrate the importance of IL-27 for the physiological control of immunopathology and the potential value of well-timed IL-27 application to treat life-threatening inflammation during lung infection.

【 授权许可】

CC BY