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Citation: Liu FDM, Kenngott EE, Schr?ter MF, K?hl A, Jennrich S, et al. (2014) Timed Action of IL-27 Protects from Immunopathology while Preserving Defense in Influenza. PLoS Pathog 10(5): e1004110. doi:10.1371/journal.ppat.1004110
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.
Author Summary
Annual epidemics of influenza result in 3 to 5 million cases of severe illness and approximately 300,000 deaths around the world. Although most patients infected with normal circulating influenza A viruses recover from the illness, complications arise during infections with highly pathogenic strains of the virus, resulting in increased mortality associated with severe immunopathology and acute respiratory distress. Previous studies suggested a major contribution of the vigorous immune response to lung damage. How the immune system constrains the negative impact of inflammation might therefore be of significant importance for future therapies. Our study in a mouse model of influenza shows that the cytokine IL-27 plays a crucial role in survival by protecting against lung damage. Its actions include regulation of innate (neutrophil influx) and adaptive (inflammatory cytokine production of T cells) arms of immunity during the acute respiratory infection. The data also suggest a therapeutic potential of IL-27, as mice treated with recombinant cytokine at later stages of infection exhibited decreased immunopathology and showed improved survival. The findings uncover an important role of IL-27 in limiting the collateral damages of anti-viral immunity and provide initial evidence that these mechanisms might be exploited for the management of severe immunopathology after infection.
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.
Author Summary
Annual epidemics of influenza result in 3 to 5 million cases of severe illness and approximately 300,000 deaths around the world. Although most patients infected with normal circulating influenza A viruses recover from the illness, complications arise during infections with highly pathogenic strains of the virus, resulting in increased mortality associated with severe immunopathology and acute respiratory distress. Previous studies suggested a major contribution of the vigorous immune response to lung damage. How the immune system constrains the negative impact of inflammation might therefore be of significant importance for future therapies. Our study in a mouse model of influenza shows that the cytokine IL-27 plays a crucial role in survival by protecting against lung damage. Its actions include regulation of innate (neutrophil influx) and adaptive (inflammatory cytokine production of T cells) arms of immunity during the acute respiratory infection. The data also suggest a therapeutic potential of IL-27, as mice treated with recombinant cytokine at later stages of infection exhibited decreased immunopathology and showed improved survival. The findings uncover an important role of IL-27 in limiting the collateral damages of anti-viral immunity and provide initial evidence that these mechanisms might be exploited for the management of severe immunopathology after infection.