title: Timed action of IL-27 protects from immunopathology while preserving defense in influenza.
abstract: 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.
authors.affiliation: Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin, Germany; Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Francesca Diane M
authors.initials: FD
authors.lastname: Liu
authors.affiliation: Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Elisabeth E
authors.initials: EE
authors.lastname: Kenngott
authors.affiliation: Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Micha F
authors.initials: MF
authors.lastname: Schröter
authors.affiliation: Research Center ImmunoSciences (RCIS), Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Kühl
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Silke
authors.initials: S
authors.lastname: Jennrich
authors.affiliation: Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Watzlawick
authors.affiliation: Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Hoffmann
authors.affiliation: Robert Koch-Institut, Berlin, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Wolff
authors.affiliation: Robert Koch-Institut, Berlin, Germany.
authors.forename: Stephen
authors.initials: S
authors.lastname: Norley
authors.affiliation: Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Scheffold
authors.affiliation: Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Stumhofer
authors.affiliation: Department of Inflammation Research, Amgen Inc., Thousand Oaks, California, United States of America.
authors.forename: Christiaan J M
authors.initials: CJ
authors.lastname: Saris
authors.affiliation: Department of Experimental Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Jan M
authors.initials: JM
authors.lastname: Schwab
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Hunter
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Gudrun F
authors.initials: GF
authors.lastname: Debes
authors.affiliation: Deutsches Rheuma-Forschungszentrum and Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Alf
authors.initials: A
authors.lastname: Hamann
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D019610:Cytoprotection / Q000235:genetics / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D009980:Influenza A virus / Q000276:immunology*; D007378:Interleukins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology*; D018121:Receptors, Cytokine / Q000235:genetics; D018123:Receptors, Interleukin; D012141:Respiratory Tract Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D013997:Time Factors
chemical_list: C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D007378:Interleukins; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin