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Extracellular histones in tissue injury and inflammation

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Abstract

Neutrophil NETosis is an important element of host defense as it catapults chromatin out of the cell to trap bacteria, which then are killed, e.g., by the chromatin’s histone component. Also, during sterile inflammation TNF-alpha and other mediators trigger NETosis, which elicits cytotoxic effects on host cells. The same mechanism should apply to other forms of regulated necrosis including pyroptosis, necroptosis, ferroptosis, and cyclophilin D-mediated regulated necrosis. Beyond these toxic effects, extracellular histones also trigger thrombus formation and innate immunity by activating Toll-like receptors and the NLRP3 inflammasome. Thereby, extracellular histones contribute to the microvascular complications of sepsis, major trauma, small vessel vasculitis as well as acute liver, kidney, brain, and lung injury. Finally, histones prevent the degradation of extracellular DNA, which promotes autoimmunization, anti-nuclear antibody formation, and autoimmunity in susceptible individuals. Here, we review the current evidence on the pathogenic role of extracellular histones in disease and discuss how to target extracellular histones to improve disease outcomes.

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Acknowledgement

A.R and H.J.A. were supported by the Deutsche Forschungsgemeinschaft GRK 1202. HJA by AN372/14-1.

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Authors and Affiliations

  1. Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066, Epalinges, Switzerland

    Ramanjaneyulu Allam

  2. Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Ziemssenstr. 1, 80336, Munich, Germany

    Santhosh V. R. Kumar, Murthy N. Darisipudi & Hans-Joachim Anders

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  1. Ramanjaneyulu Allam
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Allam, R., Kumar, S.V.R., Darisipudi, M.N. et al. Extracellular histones in tissue injury and inflammation. J Mol Med 92, 465–472 (2014). https://doi.org/10.1007/s00109-014-1148-z

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