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

Nature Immunology volume 15, pages 1017–1025 (2014)Cite this article

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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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Figure 1: Hyphae selectively induce NETosis.
Figure 2: Single bacteria do not induce the release of NETs.
Figure 3: Selective NETosis is critical for clearance of hyphae in vivo.
Figure 4: Only hyphae trigger translocation of NE to the nucleus.
Figure 5: Phagocytosis inhibits NETosis via sequestration of NE.
Figure 6: The phagocytic receptor dectin-1 negatively regulates NETosis.
Figure 7: Deregulation of NET release leads to pathology.

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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.

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Authors and Affiliations

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

    Nora Branzk, Aleksandra Lubojemska, Qian Wang & Venizelos Papayannopoulos

  2. Aberdeen Fungal Group, University of Aberdeen, Institute of Medical Sciences, Aberdeen, Foresterhill, UK

    Sarah E Hardison & Gordon D Brown

  3. Division of Mycobacterial Research, Medical Research Council National Institute for Medical Research, London, Mill Hill, 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.

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Correspondence to Venizelos Papayannopoulos.

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Integrated supplementary information

Supplementary Figure 1 Hyphae induce NET release, but yeast do not.

(a) NET release by human peripheral neutrophils stimulated with a hgc1Δ yeast-locked C. albicans mutant (yeast) or pre-formed WT C. albicans hyphae with or without plasma. MOI = 10. Scale bars = 50 μm. (b) Quantification of NET release of human peripheral neutrophils stimulated with preformed WT C. albicans hyphae or hgc1Δ yeast-locked C. albicans with 3% plasma. Percentage (%) of Sytox positive events over total number of neutrophils. Statistics by one-way ANOVA, followed by Tukey’s multiple comparison post test: * p<0.0001. (c) NET release by human peripheral neutrophils stimulated with heat-killed C. albicans hyphae..(d) Quantification of NET release by neutrophils stimulated with heat inactivated or untreated C. albicans hyphae. Percentage (%) of Sytox positive events over total number of neutrophils. Statistics by one-way ANOVA, followed by Tukey’s multiple comparison post test: * p<0.0001. (e) Peripheral human neutrophils attached to the bottom of a modified transwell membrane 1 h post incubation and after removal followed by 3 rinses with PBS. Nuclei stained with DAPI (blue). (f) Quantification of NET release after direct stimulation of human peripheral neutrophils with C. albicans hgc1Δ yeast, separated by a suspended transwell that does not allow direct contact but exchange of soluble factors. Percentage (%) of Sytox positive events over total number of neutrophils. Scale bars (a, c) 50 μm. Statistics by one-way ANOVA, followed by Tukey’s multiple comparison post test: NS p>0.5, * p<0.0001. Data are representative of at least three independent experiments. US; unstimulated.

Supplementary Figure 2 Small hyphae fragments fail to induce NET release.

(a, b) Confocal microscopy 0.8 μm z-stack series (z:1 to z:6 or z:9) of human peripheral neutrophils stimulated with (a) fragmented heat-killed C. albicans hyphae (MOI = equivalent of 10 intact hyphae) or (b) intact heat-killed C. albicans hyphae (MOI = 10). Fixed 60 min post stimulation. Stained for MPO (green), C. albicans (red) and DNA (DAPI, blue). (b) depicts a neutrophil that has just released NETs. Scale bars (a, b), 5 μm. Data are representative of at least three independent experiments.

Supplementary Figure 3 A. fumigatus filaments and aggregates induce NETs.

Human peripheral neutrophils stimulated with A. fumigatus with or without 3% plasma. Hyphae were preformed in RPMI medium. Aggregates form in presence of plasma. DNA (Sytox) stain of NET release 4 h post stimulation. Scale bars, 50 μm. Data are representative of at least three independent experiments.

Supplementary Figure 4 NADPH oxidase–deficient mice are susceptible to hgc1Δ yeast-locked C. albicans.

(a) Weight of WT (C57BL/6) and NADPH oxidase KO mice after infection with 1x104 c.f.u. of hgc1Δ yeast locked C. albicans (n=5) and WT C. albicans (n=5). Weight normalized to starting weight at d0. Statistics by two-way ANOVA, followed by Sidak’s multiple comparison post test: NS p>0.5, * p<0.0001. Data are representative of two independent experiments. b) Overview of antimicrobial strategies of WT (C57BL/6), dectin-1 deficient and NADPH oxidase deficient mice after stimulation with WT or yeast locked C. albicans. (error bars (b), s.d.)

Supplementary Figure 5 Yeast and hyphae induce similar signaling.

(a) Syk and ERK kinase activation in human peripheral neutrophils stimulated with WT C. albicans hyphae or hgc1Δ yeast-locked mutant C. albicans for the indicated times and assessed by immunoblotting. (b) Production of reactive oxygen species (ROS) by human peripheral neutrophils after stimulation with WT C. albicans hyphae or hgc1Δ yeast-locked mutant C. albicans. Data are representative of at least three independent experiments. US, unstimulated; LU, luminescence units.

Supplementary Figure 6 Increased NET release and tissue damage in the lungs of dectin-1-deficient mice.

(a) NET release in lungs of WT (C57BL/6) and dectin-1 deficient mice infected with 1x105 c.f.u. WT C. albicans 24 hours post infection stained for DNA (DAPI), MPO and citrullinated histone H3 (H3-cit) and analyzed by immunofluorescence confocal microscopy. Scale bars, 20 μm. (b) C. albicans load in the lung 12 h post infection (n=3). Statistics by unpaired t test: NS p>0.05 (c) Overview of neutrophil infiltration. Lungs of WT (C57BL/6) and dectin-1 deficient mice infected with of 3x106 c.f.u. hgc1Δ yeast-locked C. albicans. Fixation and staining of lung sections with hematoxylin and eosin (HE) 36 hours post infection. Scale bars, 1 mm. (d) TNFα levels in lung sections of WT (C57BL/6) and dectin-1 deficient mice infected with of 3x106 c.f.u. hgc1Δ yeast-locked C. albicans 36 h post infection, stained by immunohistochemistry with an antibody against TNFα (brown) and hematoxylin (DNA, blue). Scale bars, 50 μm. Data are representative of two independent experiments. UT, untreated.

Supplementary Figure 7 Increased NET-mediated tissue damage in dectin-1-deficient mice.

(a) Lungs of WT (C57BL/6) and dectin-1 deficient mice infected with of 3x106 c.f.u. hgc1Δ yeast-locked C. albicans. Fixation and staining of lung sections with hematoxylin and eosin (HE) 36 hours post infection. Tissue damage manifested in fibrin deposition and bleeding. Arrows indicate fibrin deposition and bleeding. Bottom panels depict higher magnification of areas indicated by black dotted squares. Data are representative of two independent experiments. UT, untreated. Lower panel: magnification detail in upper panel. (b) Overview of causes of pathology in WT (C57BL/6) and dectin-1-deficient mice after infection with hgc1Δ yeast-locked C. albicans. (c) Phagocytosed yeast particles drive the translocation of NE to the phagosome via fusion with azurophilic granules, sequestering NE away from the nucleus. In contrast, in the absence of a phagosome during the response to hyphae, NE translocates from azurophilic granules to the nucleus, processing histones to drive chromatin decondensation. By inhibiting NETosis, phagocytosis prevents tissue damage caused by uncontrolled NET release. Scale bars (a) 50 μm

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 (PDF 7247 kb)

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). (MP4 30051 kb)

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). (MP4 32445 kb)

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Branzk, N., Lubojemska, A., Hardison, S. et al. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat Immunol 15, 1017–1025 (2014). https://doi.org/10.1038/ni.2987

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