Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense
Open accessAbstract
Although eosinophils are considered useful in defense mechanisms against parasites, their exact function in innate immunity remains unclear. The aim of this study is to better understand the role of eosinophils within the gastrointestinal immune system. We show here that lipopolysaccharide from Gram-negative bacteria activates interleukin-5 (IL-5)- or interferon-gamma-primed eosinophils to release mitochondrial DNA in a reactive oxygen species-dependent manner, but independent of eosinophil death. Notably, the process of DNA release occurs rapidly in a catapult-like manner--in less than one second. In the extracellular space, the mitochondrial DNA and the granule proteins form extracellular structures able to bind and kill bacteria both in vitro and under inflammatory conditions in vivo. Moreover, after cecal ligation and puncture, Il5-transgenic but not wild-type mice show intestinal eosinophil infiltration and extracellular DNA deposition in association with protection against microbial sepsis. These data suggest a previously undescribed mechanism of eosinophil-mediated innate immune responses that might be crucial for maintaining the intestinal barrier function after inflammation-associated epithelial cell damage, preventing the host from uncontrolled invasion of bacteria.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
SLE damage was evaluated using the Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index (SDI).
“SLE damages were evaluated using the Systemic Lupus International Collaborating Clinics (SLICC)/ACR damage index (SDI) (Supplementary Table 2) (7,8).”
From Identification of Mitofusin 1 and Complement Component 1q Subcomponent Binding Protein as Mitochondrial Targets in Systemic Lupus Erythematosus (2022) · cites this paper as [7]
Different cellular lineages may extrude their mitochondria upon activation.
“Different cellular lineages (10–18) may extrude their mitochondria upon activation.”
From Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA (2019) · cites this paper as [13]
NET-like structures can be released by cells other than neutrophils, including mast cells, eosinophils, and basophils.
“NET-like structures can be released by cells other than neutrophils, including mast cells [732], eosinophils [733], and basophils [734].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [733]
Cites
Neutrophil Extracellular Traps Kill Bacteria
Brinkmann, V., Reichard, U., Goosmann, C., Fauler, B., Uhlemann, Y., Weiss, D. S., Weinrauch, Y., & Zychlinsky, A. (2004) · Science · doi:10.1126/science.1092385 · Cited by 10,268 · see citing works
Novel cell death program leads to neutrophil extracellular traps
Fuchs, T. A., Abed, U., Goosmann, C., Hurwitz, R., Schulze, I., Wahn, V., Weinrauch, Y., Brinkmann, V., & Zychlinsky, A. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200606027 · Cited by 3,197 · see citing works
Podolsky, D. K. (2002) · New England Journal of Medicine · doi:10.1056/nejmra020831 · Cited by 3,183 · see citing works
Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood
Clark, S. R., Ma, A. C., Tavener, S. A., McDonald, B., Goodarzi, Z., Kelly, M. M., Patel, K. D., Chakrabarti, S., McAvoy, E., Sinclair, G. D., et al. (2007) · Nature Medicine · doi:10.1038/nm1565 · Cited by 2,309 · see citing works
Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis
Yousefi, S., Perozzo, R., Schmid, I., Ziemiecki, A., Schaffner, T. J., Scapozza, L., Brunner, T., & Simon, H. (2006) · Nature Cell Biology · doi:10.1038/ncb1482 · Cited by 1,300 · see citing works
Self-citationBeneficial suicide: why neutrophils die to make NETs
Brinkmann, V., & Zychlinsky, A. (2007) · Nature Reviews Microbiology · doi:10.1038/nrmicro1710 · Cited by 937 · see citing works
Rothenberg, M. E. (1998) · New England Journal of Medicine · doi:10.1056/nejm199805283382206 · Cited by 837 · see citing works
von Köckritz‐Blickwede, M., Goldmann, O., Thulin, P., Heinemann, K., Norrby‐Teglund, A., Rohde, M., & Medina, E. (2008) · Blood · doi:10.1182/blood-2007-07-104018 · Cited by 553 · see citing works
Podolsky, D. K. (1991) · New England Journal of Medicine · doi:10.1056/nejm199110033251406 · Cited by 549 · see citing works
Jaillon, S., Peri, G., Delneste, Y., Frémaux, I., Doni, A., Moalli, F., Garlanda, C., Romani, L. R., Gascan, H., Bellocchio, S., et al. (2007) · The Journal of Experimental Medicine · doi:10.1084/jem.20061301 · Cited by 533 · see citing works
Martinelli, S., Urosevic, M., Daryadel, A., Oberholzer, P. A., Baumann, C. K., Fey, M. F., Dummer, R., Simon, H., & Yousefi, S. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m405883200 · Cited by 294 · see citing works
Self-citationJacobsen, E. A., Ochkur, S. I., Pero, R. S., Taranova, A. G., Protheroe, C. A., Colbert, D. C., Lee, N. A., & Lee, J. J. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20071840 · Cited by 263 · see citing works
Self-citationConus, S., Perozzo, R., Reinheckel, T., Peters, C., Scapozza, L., Yousefi, S., & Simon, H. (2008) · The Journal of Experimental Medicine · doi:10.1084/jem.20072152 · Cited by 262 · see citing works
Self-citationAnti-CD20 (rituximab) treatment improves atopic eczema
Simon, D., Radonjic‐Hoesli, S., Kostylina, G., Yawalkar, N., & Simon, H. (2008) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2007.11.016 · Cited by 253 · see citing works
Self-citationLee, N. A., McGarry, M. P., Larson, K. A., Horton, M. A., Kristensen, A. B., & Lee, J. J. (1997) · The Journal of Immunology · doi:10.4049/jimmunol.158.3.1332 · Cited by 240 · see citing works
Self-citationYousefi, S., Hoessli, D. C., Blaser, K., et al. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.183.4.1407 · Cited by 235 · see citing works
Self-citationvon Gunten, S., Yousefi, S., Seitz, M., Jakob, S. M., Schaffner, T. J., Seger, R. A., Takala, J. A., Villiger, P. M., & Simon, H. (2005) · Blood · doi:10.1182/blood-2004-10-4112 · Cited by 217 · see citing works
Self-citationAltznauer, F., Martinelli, S., Yousefi, S., Thürig, C., Schmid, I., Conway, E. M., Schöni, M. H., VOGT, P. R., Mueller, C., Fey, M. F., et al. (2004) · The Journal of Experimental Medicine · doi:10.1084/jem.20032033 · Cited by 201 · see citing works
Self-citationProtein-tyrosine phosphorylation regulates apoptosis in human eosinophils and neutrophils.
Yousefi, S., Green, D. R., Blaser, K., et al. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.23.10868 · Cited by 193 · see citing works
Self-citationSimon, D., & Simon, H. (2007) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2007.02.010 · Cited by 141 · see citing works
Self-citationThe physiological and pathophysiological roles of eosinophils in the gastrointestinal tract
Straumann, A., & Simon, H. (2003) · Allergy · doi:10.1046/j.1398-9995.2003.00382.x · Cited by 126 · see citing works
Self-citationMelo, R. C. N., Spencer, L. A., Dvořàk, A. M., et al. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0707503 · Cited by 121 · see citing works
Neutrophil apoptosis mediated by nicotinic acid receptors (GPR109A)
Kostylina, G., Simon, D., Fey, M. F., Yousefi, S., & Simon, H. (2007) · Cell Death and Differentiation · doi:10.1038/sj.cdd.4402238 · Cited by 119 · see citing works
Self-citationA record-breaking pollen catapult
Edwards, J., Whitaker, D., Klionsky, S., et al. (2005) · Nature · doi:10.1038/435164a · Cited by 119 · see citing works
Activated eosinophils and interleukin 5 expression in early recurrence of Crohn's disease.
Dubucquoi, S., Janin, A., Klein, O., Desreumaux, P., Quandalle, P. A., Cortot, A., Capron, M., & Colombel, J. F. (1995) · Gut · doi:10.1136/gut.37.2.242 · Cited by 115 · see citing works
CD40 and CD80/86 Act Synergistically to Regulate Inflammation and Mortality in Polymicrobial Sepsis
Nolan, A., Weiden, M. D., Kelly, A., et al. (2007) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200703-515oc · Cited by 102 · see citing works
Self-citationShigella flexneri is trapped in polymorphonuclear leukocyte vacuoles and efficiently killed
Mandić-Mulec, I., Weiss, J. P., & Zychlinsky, A. (1997) · Infection and Immunity · doi:10.1128/iai.65.1.110-115.1997 · Cited by 73 · see citing works
Interactions of eosinophil granule proteins with skin
Davis, M. D. P., Plager, D. A., George, T. J., et al. (2003) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2003.08.028 · Cited by 52 · see citing works
cIAP‐2 and survivin contribute to cytokine‐mediated delayed eosinophil apoptosis
Vassina, E. M., Yousefi, S., Simon, D., Zwicky, C., Conus, S., & Simon, H. (2006) · European Journal of Immunology · doi:10.1002/eji.200635943 · Cited by 49 · see citing works
Self-citationInterleukin‐5 participates in the pathogenesis of ileitis in SAMP1/Yit mice
Takedatsu, H., Mitsuyama, K., Matsumoto, S., Handa, K., Suzuki, A., Takedatsu, H., Funabashi, H., Okabe, Y., Hara, T., Toyonaga, A., et al. (2004) · European Journal of Immunology · doi:10.1002/eji.200324680 · Cited by 45 · see citing works
Simon, H., Weber, M., Becker, E. M., et al. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.165.7.4069 · Cited by 45 · see citing works
Self-citationIn Situ Interleukin 5 Gene Expression in Pediatric Crohn's Disease
Fromont, G., Brousse, N., Cézard, J., et al. (1997) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/00005176-199705000-00015 · Cited by 10 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., Agostinis, P., Alnemri, E. S., Altucci, L., Amelio, I., Andrews, D. W., et al. (2018) · Cell Death & Differentiation · doi:10.1038/s41418-017-0012-4 · Cited by 6,680 · see citing works
Self-citationGalluzzi, L., Vitale, I., Abrams, J. M., Alnemri, E. S., Baehrecke, E. H., Blagosklonny, M. V., Dawson, T. M., Dawson, V. L., El-Deiry, W. S., Fulda, S., et al. (2012) · Cell Death & Differentiation · doi:10.1038/cdd.2011.96 · Cited by 2,421 · see citing works
Self-citationNeutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps
Papayannopoulos, V., Metzler, K. D., Hakkim, A., & Zychlinsky, A. (2010) · Journal of Cell Biology · doi:10.1083/jcb.201006052 · Cited by 2,103 · see citing works
Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo
Yipp, B. G., Petri, B., Salina, D., Jenne, C. N., Scott, B. N. V., Zbytnuik, L. D., Pittman, K., Asaduzzaman, M., Wu, K., Meijndert, H. C., et al. (2012) · Nature Medicine · doi:10.1038/nm.2847 · Cited by 1,169 · see citing works
Pilsczek, F. H., Salina, D., Poon, K. K. H., Fahey, C., Yipp, B. G., Sibley, C. D., Robbins, S. M., Green, F. H. Y., Surette, M. G., Sugai, M., et al. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000675 · Cited by 1,114 · see citing works
Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps
Yousefi, S., Mihalache, C., Kozlowski, E., Schmid, I., & Simon, H. U. (2009) · Cell Death & Differentiation · doi:10.1038/cdd.2009.96 · Cited by 1,036 · see citing works
Self-citationOrigins, structures, and functions of circulating DNA in oncology
Thierry, A. R., El Messaoudi, S., Gahan, P. B., Anker, P., & Stroun, M. (2016) · Cancer and Metastasis Reviews · doi:10.1007/s10555-016-9629-x · Cited by 818 · see citing works
Mitochondria: master regulators of danger signalling
Galluzzi, L., Kepp, O., & Kroemer, G. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3479 · Cited by 733 · see citing works
Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation
Krysko, D. V., Agostinis, P., Krysko, O., Garg, A. D., Bachert, C., Lambrecht, B. N., & Vandenabeele, P. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.01.005 · Cited by 680 · see citing works
NETs: a new strategy for using old weapons
Papayannopoulos, V., & Zychlinsky, A. (2009) · Trends in Immunology · doi:10.1016/j.it.2009.07.011 · Cited by 634 · see citing works
NETosis: Molecular Mechanisms, Role in Physiology and Pathology
Vorobjeva, N. V., & Chernyak, B. V. (2020) · Biochemistry (Moscow) · doi:10.1134/s0006297920100065 · Cited by 559 · see citing works
Caielli, S., Athale, S., Domic, B., Murat, E., Chandra, M., Banchereau, R., Baisch, J., Phelps, K., Clayton, S., Gong, M., et al. (2016) · Journal of Experimental Medicine · doi:10.1084/jem.20151876 · Cited by 501 · see citing works
Mitochondria Know No Boundaries: Mechanisms and Functions of Intercellular Mitochondrial Transfer
Torralba, D., Baixauli, F., & Sánchez-Madrid, F. (2016) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2016.00107 · Cited by 440 · see citing works
Pinti, M., Cevenini, E., Nasi, M., De Biasi, S., Salvioli, S., Monti, D., Benatti, S., Gibellini, L., Cotichini, R., Stazi, M. A., et al. (2014) · European Journal of Immunology · doi:10.1002/eji.201343921 · Cited by 409 · see citing works
Cell-Free DNA as a Biomarker in Autoimmune Rheumatic Diseases
Duvvuri, B., & Lood, C. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.00502 · Cited by 282 · see citing works
Iske, J., Seyda, M., Heinbokel, T., Maenosono, R., Minami, K., Nian, Y., Quante, M., Falk, C. S., Azuma, H., Martin, F., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18039-x · Cited by 211 · see citing works
NADPH Oxidase–Independent Formation of Extracellular DNA Traps by Basophils
Morshed, M., Hlushchuk, R., Simon, D., Walls, A. F., Obata-Ninomiya, K., Karasuyama, H., Djonov, V., Eggel, A., Kaufmann, T., Simon, H.-U., et al. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1303418 · Cited by 161 · see citing works
Self-citationArtificial Mitochondria Transfer: Current Challenges, Advances, and Future Applications
Caicedo, A., Aponte, P. M., Cabrera, F., Hidalgo, C., & Khoury, M. (2017) · Stem Cells International · doi:10.1155/2017/7610414 · Cited by 150 · see citing works
ROS and glutathionylation balance cytoskeletal dynamics in neutrophil extracellular trap formation
Stojkov, D., Amini, P., Oberson, K., Sokollik, C., Duppenthaler, A., Simon, H.-U., & Yousefi, S. (2017) · Journal of Cell Biology · doi:10.1083/jcb.201611168 · Cited by 142 · see citing works
Self-citationccf-mtDNA as a Potential Link Between the Brain and Immune System in Neuro-Immunological Disorders
Gambardella, S., Limanaqi, F., Ferese, R., Biagioni, F., Campopiano, R., Centonze, D., & Fornai, F. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01064 · Cited by 141 · see citing works
Opposing roles of eosinophils in cancer
Simon, S. C. S., Utikal, J., & Umansky, V. (2019) · Cancer Immunology, Immunotherapy · doi:10.1007/s00262-018-2255-4 · Cited by 128 · see citing works
Emerging Roles for Eosinophils in the Tumor Microenvironment
Reichman, H., Karo-Atar, D., & Munitz, A. (2016) · Trends in Cancer · doi:10.1016/j.trecan.2016.10.002 · Cited by 116 · see citing works
Eosinophil Deficiency Compromises Lung Defense against Aspergillus fumigatus
Lilly, L. M., Scopel, M., Nelson, M. P., Burg, A. R., Dunaway, C. W., & Steele, C. (2014) · Infection and Immunity · doi:10.1128/iai.01172-13 · Cited by 89 · see citing works
Mast Cells in Allergic and Inflammatory Diseases
Sismanopoulos, N., Delivanis, D.-A., Alysandratos, K.-D., Angelidou, A., Therianou, A., Kalogeromitros, D., & C. Theoharides, T. (2012) · Current Pharmaceutical Design · doi:10.2174/138161212800165997 · Cited by 87 · see citing works
Antimicrobial proteins: from old proteins, new tricks
Smith, V. J., & Dyrynda, E. A. (2015) · Molecular Immunology · doi:10.1016/j.molimm.2015.08.009 · Cited by 85 · see citing works
Ortmann, W., & Kolaczkowska, E. (2018) · Cell and Tissue Research · doi:10.1007/s00441-017-2751-4 · Cited by 80 · see citing works
Becker, Y., Loignon, R.-C., Julien, A.-S., Marcoux, G., Allaeys, I., Lévesque, T., Rollet-Labelle, E., Benk-Fortin, H., Cloutier, N., Melki, I., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-40900-3 · Cited by 75 · see citing works
Autoantibodies in Systemic Lupus Erythematosus Target Mitochondrial RNA
Becker, Y., Marcoux, G., Allaeys, I., Julien, A.-S., Loignon, R.-C., Benk-Fortin, H., Rollet-Labelle, E., Rauch, J., Fortin, P. R., & Boilard, E. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01026 · Cited by 59 · see citing works
Becker, Y. L. C., Gagné, J., Julien, A., Lévesque, T., Allaeys, I., Gougeard, N., Rubio, V., Boisvert, F., Jean, D., Wagner, E., et al. (2022) · Arthritis & Rheumatology · doi:10.1002/art.42082 · Cited by 26 · see citing works
Huang, S. U.-S., & O’Sullivan, K. M. (2022) · doi:10.20944/preprints202203.0021.v1 · Cited by 65 · see citing works
- Authors
- Yousefi, S., Gold, J. A., Andina, N., Lee, J. J., Kelly, A. M., Kozlowski, E., Schmid, I., Straumann, A., Reichenbach, J., Gleich, G. J., & Simon, H.-U.
- Affiliations
- Oregon Health & Science University (US)
- University of Bern (CH)
- Mayo Clinic (US)
- University of Zurich (CH)
- University of Utah (US)
- Corresponding author
- Simon, Hans-Uwe
- ORCID
- Venue
- Nature Medicine
- Published
- 2008-08-10
- Volume
- 14
- Issue
- 9
- Pages
- 949-953
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2139719760
- Cited by
- 967
- References
- 32
- Citations by year
- 2026: 32 · 2025: 33 · 2024: 50 · 2023: 57 · 2022: 74 · 2021: 84 · 2020: 78 · 2019: 74 · 2018: 65 · 2017: 55 · 2016: 49 · 2015: 60 · 2014: 56 · 2013: 41 · 2012: 54
- FWCI
- 14.32
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion)
- BORIS (University Library Bern) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
- Stanley Thomas Johnson Stiftung
- National Institute of Allergy and Infectious Diseases (R01AI067522)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Health Sciences › Medicine › Physiology › Asthma and respiratory diseases
- Keywords
- eosinophils, mitochondrial DNA release, antibacterial defense, innate immunity, intestinal immunity, lipopolysaccharide, IL-5, interferon-gamma, reactive oxygen species, granule proteins, extracellular DNA, bacterial sepsis, intestinal barrier, cecal ligation and puncture, Gram-negative bacteria
- MeSH terms
- Animals, Bacteria, Cell Differentiation, DNA, Mitochondrial, Eosinophils, Gastrointestinal Diseases, Humans, Mice, Transgenic, Interleukin-5, Reactive Oxygen Species, In Situ Hybridization, Fluorescence, Microscopy, Confocal, Sepsis, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
