Neutralizing the pathological effects of extracellular histones with small polyanions

Connor H. O’ Meara, Lucy A. Coupland, Farzaneh Kordbacheh, Benjamin J. C. Quah, Chih-Wei Chang, David A. Simon Davis, Anna Bezos, Anna M. Browne, Craig Freeman, Dillon J. Hammill, Pradeep Chopra, Gergely Pipa, Paul D. Madge, Esther Gallant, Courtney Segovis, Angela F. Dulhunty, Leonard F. Arnolda, Imogen Mitchell, Levon M. Khachigian, Ross W. Stephens, Mark Itzstein and Christopher R. Parish ()
Additional contact information
Connor H. O’ Meara: The Australian National University
Lucy A. Coupland: The Australian National University
Farzaneh Kordbacheh: The Australian National University
Benjamin J. C. Quah: The Australian National University
Chih-Wei Chang: Griffith University
David A. Simon Davis: The Australian National University
Anna Bezos: The Australian National University
Anna M. Browne: The Australian National University
Craig Freeman: The Australian National University
Dillon J. Hammill: The Australian National University
Pradeep Chopra: Griffith University
Gergely Pipa: Griffith University
Paul D. Madge: Griffith University
Esther Gallant: Australian National University
Courtney Segovis: Australian National University
Angela F. Dulhunty: Australian National University
Leonard F. Arnolda: Illawarra Health and Medical Research Institute
Imogen Mitchell: The Canberra Hospital
Levon M. Khachigian: University of New South Wales
Ross W. Stephens: The Australian National University
Mark Itzstein: Griffith University
Christopher R. Parish: The Australian National University

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Extracellular histones in neutrophil extracellular traps (NETs) or in chromatin from injured tissues are highly pathological, particularly when liberated by DNases. We report the development of small polyanions (SPAs) (~0.9–1.4 kDa) that interact electrostatically with histones, neutralizing their pathological effects. In vitro, SPAs inhibited the cytotoxic, platelet-activating and erythrocyte-damaging effects of histones, mechanistic studies revealing that SPAs block disruption of lipid-bilayers by histones. In vivo, SPAs significantly inhibited sepsis, deep-vein thrombosis, and cardiac and tissue-flap models of ischemia-reperfusion injury (IRI), but appeared to differ in their capacity to neutralize NET-bound versus free histones. Analysis of sera from sepsis and cardiac IRI patients supported these differential findings. Further investigations revealed this effect was likely due to the ability of certain SPAs to displace histones from NETs, thus destabilising the structure. Finally, based on our work, a non-toxic SPA that inhibits both NET-bound and free histone mediated pathologies was identified for clinical development.

Date: 2020
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DOI: 10.1038/s41467-020-20231-y

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