Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones

By M. Saffarzadeh, C. Juenemann, M. Queisser, G. Lochnit, G. Barreto, S. Galuska, J. Lohmeyer, K. Preissner. PLoS ONE, 2012

1,258 citations recorded by the source corpus.

Neutrophils play an important role in innate immunity by defending the host organism against invading microorganisms. Antimicrobial activity of neutrophils is mediated by release of antimicrobial peptides, phagocytosis as well as formation of neutrophil extracellular traps (NET). These structures are composed of DNA, histones and granular proteins such as neutrophil elastase and myeloperoxidase. This study focused on the influence of NET on the host cell functions, particularly on human alveolar epithelial cells as the major cells responsible for gas exchange in the lung. Upon direct interaction with epithelial and endothelial cells, NET induced cytotoxic effects in a dose-dependent manner, and digestion of DNA in NET did not change NET-mediated cytotoxicity. Pre-incubation of NET with antibodies against histones, with polysialic acid or with myeloperoxidase inhibitor but not with elastase inhibitor reduced NET-mediated cytotoxicity, suggesting that histones and myeloperoxidase are responsible for NET-mediated cytotoxicity. Although activated protein C (APC) did decrease the histone-induced cytotoxicity in a purified system, it did not change NET-induced cytotoxicity, indicating that histone-dependent cytotoxicity of NET is protected against APC degradation. Moreover, in LPS-induced acute lung injury mouse model, NET formation was documented in the lung tissue as well as in the bronchoalveolar lavage fluid. These data reveal the important role of protein components in NET, particularly histones, which may lead to host cell cytotoxicity and may be involved in lung tissue destruction.

Subfields: Immunology

View Paper: https://www.semanticscholar.org/paper/5fd97d0ad31eed78ca010578cf1ed70648058109

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In Immunology

1. P. Kubes
2. B. Yipp
3. V. Brinkmann
4. C. Rosales
5. Arturo Zychlinsky
6. B. McDonald
7. C. Jenne
8. M. Egeblad

Citations in the corpus

• Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? (2018, background): “Reciprocally, NETs induce endothelial cell activation through NET-derived proteases, histones, and defensins (Saffarzadeh et al., 2012), creating a positive feedback loop for thrombosis.”
• TFOS DEWS II pathophysiology report. (2017, background): “These comprise extracellular webs or scaffolds containing decondensed chromatin, histones, neutrophil elastase and antimicrobial peptides such as cathelicidin, each of which individually may be toxic for epithelial cells [237].”
• Neutrophil extracellular traps: Is immunity the second function of chromatin? (2012, background): “In addition to the proteolytic enzymes present in NETs, histones were shown to directly kill endothelial cells (Gupta et al., 2010; Saffarzadeh et al., 2012).”
• Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview (2017, background): “Autoimmunity is triggered by cPR-3(105-201), a protein complementary to human autoantigen proteinase-3.”
• Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. (2012, background): “The exact source of pathological histones in their models of sepsis was not defined, but a recent study by Saffarzadeh and colleagues suggests that NETs may be an important source of extracellular histones that mediate tissue injury (Saffarzadeh et al., 2012; Chaput and Zychlinsky, 2009).”
• Neutrophil extracellular traps in COVID-19. (2020, background): “present and stabilize a variety of oxidant enzymes in the extracellular space, including MPO, NADPH oxidase, and nitric oxide synthase (46), while serving as a source of extracellular histones that carry significant cytotoxic potential (47, 48).”
• Neutrophil extracellular traps sequester circulating tumor cells and promote metastasis. (2013, positive): “The demonstration that trapped tumor cells are able to survive and ultimately go on to form gross metastatic nodules contrasts with reports demonstrating that NETs are cytotoxic to epithelial and endothelial cells (49, 66).”