J Mol Med (2014) 92:465–472 DOI 10.1007/s00109-014-1148-z
REVIEW
Extracellular histones in tissue injury and inflammation Ramanjaneyulu Allam & Santhosh V. R. Kumar & Murthy N. Darisipudi & Hans-Joachim Anders
Received: 7 February 2014 / Revised: 16 March 2014 / Accepted: 21 March 2014 / Published online: 6 April 2014 # Springer-Verlag Berlin Heidelberg 2014
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 Tolllike 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. Keywords Chromatin . Sepsis . Acute kidney injury . Ischemia . DAMP . Neutrophil extracellular traps
Introduction Histones are important structural elements of nuclear chromatin and regulate gene transcription. By contrast, outside the R. Allam Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland S. V. R. Kumar : M. N. Darisipudi : H.
REVIEW
Extracellular histones in tissue injury and inflammation Ramanjaneyulu Allam & Santhosh V. R. Kumar & Murthy N. Darisipudi & Hans-Joachim Anders
Received: 7 February 2014 / Revised: 16 March 2014 / Accepted: 21 March 2014 / Published online: 6 April 2014 # Springer-Verlag Berlin Heidelberg 2014
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 Tolllike 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. Keywords Chromatin . Sepsis . Acute kidney injury . Ischemia . DAMP . Neutrophil extracellular traps
Introduction Histones are important structural elements of nuclear chromatin and regulate gene transcription. By contrast, outside the R. Allam Department of Biochemistry, University of Lausanne, Chemin des Boveresses 155, CH-1066 Epalinges, Switzerland S. V. R. Kumar : M. N. Darisipudi : H.
