Timed Action of IL-27 Protects from Immunopathology while Preserving Defense in Influenza
Liu, Francesca Diane M.
Kenngott, Elisabeth E.
Schröter, Micha F.
Kühl, Anja
Jennrich, Silke
Watzlawick, Ralf
Hoffmann, Ute
Wolff, Thorsten
Norley, Stephen
Scheffold, Alexander
Stumhofer, Jason S.
Saris, Christiaan J. M.
Schwab, Jan M.
Hunter, Christopher A.
Debes, Gudrun F.
Hamann, Alf
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.
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