Article | Published:

Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens

Nature Immunology volume 15, pages 10171025 (2014) | Download Citation

Abstract

Neutrophils are critical for antifungal defense, but the mechanisms that clear hyphae and other pathogens that are too large to be phagocytosed remain unknown. We found that neutrophils sensed microbe size and selectively released neutrophil extracellular traps (NETs) in response to large pathogens, such as Candida albicans hyphae and extracellular aggregates of Mycobacterium bovis, but not in response to small yeast or single bacteria. NETs were fundamental in countering large pathogens in vivo. Phagocytosis via dectin-1 acted as a sensor of microbe size and prevented NET release by downregulating the translocation of neutrophil elastase (NE) to the nucleus. Dectin-1 deficiency led to aberrant NET release and NET-mediated tissue damage during infection. Size-tailored neutrophil responses cleared large microbes and minimized pathology when microbes were small enough to be phagocytosed.

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Acknowledgements

We thank the blood donors; Y. Wang (Institute of Molecular and Cell Biology of the Agency for Science, Technology and Research) and N. Gow (University of Aberdeen) for the hgc1Δ C. albicans strain; G. Stockinger, M. Wilson and A. Zychlinsky for comments on the manuscript; E. Bernard for help with the M. bovis preparation; D. Bell for advice on microscopy; and A. Adekoya and K. Mathers for support with animal experiments. Supported by the Medical Research Council (UK) (MC_UP_1202/13 for V.P., and MC_UP_1202/11 for M.G.G.) and the Wellcome Trust.

Author information

Affiliations

  1. Division of Molecular Immunology, Medical Research Council National Institute for Medical Research, Mill Hill, London, UK.

    • Nora Branzk
    • , Aleksandra Lubojemska
    • , Qian Wang
    •  & Venizelos Papayannopoulos
  2. Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen, UK.

    • Sarah E Hardison
    •  & Gordon D Brown
  3. Division of Mycobacterial Research, Medical Research Council National Institute for Medical Research, Mill Hill, London, UK.

    • Maximiliano G Gutierrez

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Contributions

N.B. performed all experiments, except as noted below; S.E.H. and G.D.B. infected mice with A. fumigatus; N.B., A.L., Q.W. and V.P. did immunoblot analysis and neutrophil immunofluorescence microscopy; M.G.G. provided advice for and contributed to the M. bovis BCG experiments; V.P. devised and directed the study; and N.B. and V.P. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Venizelos Papayannopoulos.

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Videos

  1. 1.

    Yeast-locked C. albicans fails to induce NET release in human peripheral neutrophils.

    Time-lapse microscopy of live human peripheral neutrophils stimulated with hgc1Δ yeast-locked C. albicans. Confocal images were taken every 30 seconds. The movie represents 9 frames/second. Red: Reactive oxygen species (NBT), Green: DNA (Sytox).

  2. 2.

    Yeast-locked C. albicans induces NET release in dectin-1 blocked human peripheral neutrophils.

    Time-lapse microscopy of live human peripheral neutrophils stimulated with hgc1Δ yeast-locked C. albicans in presence of anti-dectin-1 blocking antibody. Confocal images were taken every 30 seconds. The movie represents 9 frames/second. Red: Reactive oxygen species (NBT), Green: DNA (Sytox).

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DOI

https://doi.org/10.1038/ni.2987

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