Date Published: May 8, 2014
Publisher: Public Library of Science
Author(s): Francesca Diane M. Liu, Elisabeth E. Kenngott, Micha F. Schröter, Anja Kühl, Silke Jennrich, Ralf Watzlawick, Ute Hoffmann, Thorsten Wolff, Stephen Norley, Alexander Scheffold, Jason S. Stumhofer, Christiaan J. M. Saris, Jan M. Schwab, Christopher A. Hunter, Gudrun F. Debes, Alf Hamann, Andrew Pekosz.
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.
Infection with highly pathogenic strains of influenza viruses, such as the pandemic 1918 Spanish flu, which resulted in 30–50 million deaths, is still a major threat to health , . Pathological findings suggest that the vigorous mobilization of innate and adaptive arms of host immunity upon infection leads to uncontrolled inflammation and potentially fatal lung injury . Rapid leukocyte infiltration of the lung and a subsequent cytokine storm involving the excessive production of inflammatory cytokines and chemokines have been strongly implicated in mediating lung immunopathology –. A better understanding of the factors that regulate the balance between viral clearance, tissue damage and resolution of inflammation is therefore necessary .
The tight regulation of both the induction and subsequent down-regulation of inflammatory responses during influenza is imperative in minimizing severe immunopathology. Infection with highly pathogenic strains of influenza viruses results in increased leukocytic pulmonary infiltrates and leads to the exaggerated production of inflammatory cytokines (“cytokine storm”) that causes massive inflammation with increased mortality , , . Therefore, understanding the regulatory pathways during infection not only sheds light on the mechanisms controlling the delicate balance of efficient viral clearance and disastrous immunopathology, but also reveals potential therapeutic approaches to target resolution of inflammation . Few studies have evaluated the therapeutic potential of anti-inflammatory agents in influenza; while broad-acting immunosuppressants such as corticosteroids were found to worsen the disease, a combination of antiviral therapy and anti-inflammatory non-steroidals inhibiting cyclooxygenases (COX) improved survival in mice . Similarly, targeting inhibitory pathways such as macrophage CD200, PAR2 and endothelial S1P1 receptors have been found to reduce immunopathology in influenza infection models –