Excessive neutrophil levels in the lung underlie the age-associated increase in influenza mortality

Abstract

Neutrophils clear viruses, but excessive neutrophil responses induce tissue injury and worsen disease. Aging increases mortality to influenza infection; however, whether this is due to impaired viral clearance or a pathological host immune response is unknown. Here we show that aged mice have higher levels of lung neutrophils than younger mice after influenza viral infection. Depleting neutrophils after, but not before, infection substantially improves the survival of aged mice without altering viral clearance. Aged alveolar epithelial cells (AECs) have a higher frequency of senescence and secrete higher levels of the neutrophil-attracting chemokines CXCL1 and CXCL2 during influenza infection. These chemokines are required for age-enhanced neutrophil chemotaxis in vitro. Our work suggests that aging increases mortality from influenza in part because senescent AECs secrete more chemokines, leading to excessive neutrophil recruitment. Therapies that mitigate this pathological immune response in the elderly might improve outcomes of influenza and other respiratory infections.

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Acknowledgements

The authors would like to thank Dr. Min Zhang for her expert advice in the statistical analysis of the data. We would like to thank Life Science Editors for their editorial assistance. The work was supported by NIA AG028082 to D.R.G.

Author information

U.K. and D.R.G. conceived and designed the experiments. U.K. performed the experiments with the help of C.S. and S.W. Data analysis was done by U.K. D.R.G wrote the first draft of the paper that was then edited by U.K. All authors subsequently contributed in writing and carefully reviewing the experiments and the manuscript.

Correspondence to Daniel R. Goldstein.

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The authors declare no competing interests.

Regulatory Approval

University of Michigan Institutional Animal Care and Use Committee approved the use of animals in this study. Prior to viral infection, all mice were kept in pathogen-free conditions.

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