Interleukin‐6 limits influenza‐induced inflammation and protects against fatal lung pathology

Abstract

Balancing the generation of immune responses capable of controlling virus replication with those causing immunopathology is critical for the survival of the host and resolution of influenza-induced inflammation. Based on the capacity of interleukin-6 (IL-6) to govern both optimal T-cell responses and inflammatory resolution, we hypothesised that IL-6 plays an important role in maintaining this balance. Comparison of innate and adaptive immune responses in influenza-infected wild-type control and IL-6-deficient mice revealed striking differences in virus clearance, lung immunopathology and generation of heterosubtypic immunity. Mice lacking IL-6 displayed a profound defect in their ability to mount an anti-viral T-cell response. Failure to adequately control virus was further associated with an enhanced infiltration of inflammatory monocytes into the lung and an elevated production of the pro-inflammatory cytokines, IFN-α and TNF-α. These events were associated with severe lung damage, characterised by profound vascular leakage and death. Our data highlight an essential role for IL-6 in orchestrating anti-viral immunity through an ability to limit inflammation, promote protective adaptive immune responses and prevent fatal immunopathology. Keywords: Adaptive immunity · Heterosubtypic immunity · IL-6 · Innate immunity · Pulmonary damageAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionSeasonal influenza infects 5-15% of the global population annually and results in significant morbidity and mortality [1]. Fatal infections are characterised by severe respiratory failure, which is associated with a profound early inflammatory infiltrate, lung haemorrhage and cytokine release [2][3][4]. Disease severity may Correspondence: Dr. Sarah N. Lauder e-mail: LauderSN@cf.ac.uk therefore reflect the balance between immune-mediated control of virus replication and the extent of virus-driven immunopathology. The co-ordinate activities of the innate and adaptive immune systems are likely to contribute to this balance. In order to examine this relationship, we studied the role that the cytokine, IL-6, plays in maintaining this balance. We considered this important, as IL-6 has been reported to correspond with the magnitude of strain-independent viral replication and disease severity both in animal models and in humans [5,6]. Recent data using a mouse model of influenza infection indicate that mice lacking IL-6 are less likely to survive the infection thereby implying a beneficial effect of IL-6 in controlling the infection [7].C 2013 Cardiff University. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. www.eji-journal.euThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.2614 Sarah N. Lauder et al. Eur. J. Immunol. 2013. 43: 2613-2625 The impact of IL-6 on the host respon...

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