Aging-related Atg5 defect impairs neutrophil extracellular traps formation

Immunology. 2017 Aug;151(4):417-432. doi: 10.1111/imm.12740. Epub 2017 May 16.

Abstract

Formation of neutrophil extracellular traps (NETs) is an important function of the innate immune system against infections. It has been proven that aging dysregulates immunity and impairs neutrophil function. However, the influence of aging on the ability to produce NETs has yet to be fully addressed. In this study, we tested the hypothesis that a lower level of autophagy in neutrophils from aged mice was responsible for the decrease in NET formation. We demonstrated that a broad range of Toll-like receptor 2 (TLR2) ligands could efficiently induce reactive oxygen species (ROS) -dependent NET release in young mice, but not in aged ones. We further explored that the difference between young and aged mice in TLR2 ligand-induced NETosis is the result of an Atg5 defect and subsequent impaired autophagy. Furthermore, we found that lower autophagy capacity led to not only reduced NET formation, but also increased apoptosis. Our results suggest an important role of Atg5 and autophagy in maintaining the function of NETs formation in response to infection and in regulating neutrophil death. Targeting autophagy-promoted NETs may present a therapeutic strategy to improve infection defence in an aged population.

Keywords: Atg5; aging; apoptosis; autophagy; neutrophil extracellular traps.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aging / immunology*
  • Animals
  • Autophagy*
  • Autophagy-Related Protein 5 / genetics
  • Autophagy-Related Protein 5 / metabolism*
  • Cells, Cultured
  • Extracellular Traps / immunology*
  • Immunity, Innate
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neutrophil Activation
  • Neutrophils / immunology*
  • Reactive Oxygen Species / metabolism
  • Toll-Like Receptor 2 / genetics
  • Toll-Like Receptor 2 / metabolism

Substances

  • Atg5 protein, mouse
  • Autophagy-Related Protein 5
  • Reactive Oxygen Species
  • Tlr2 protein, mouse
  • Toll-Like Receptor 2