Neutralizing the pathological effects of extracellular histones with small polyanions

• Published in: Nature communications Vol. 11; no. 1; pp. 6408 - 17
• Main Authors: Meara, Connor H. O’, Coupland, Lucy A., Kordbacheh, Farzaneh, Quah, Benjamin J. C., Chang, Chih-Wei, Simon Davis, David A., Bezos, Anna, Browne, Anna M., Freeman, Craig, Hammill, Dillon J., Chopra, Pradeep, Pipa, Gergely, Madge, Paul D., Gallant, Esther, Segovis, Courtney, Dulhunty, Angela F., Arnolda, Leonard F., Mitchell, Imogen, Khachigian, Levon M., Stephens, Ross W., von Itzstein, Mark, Parish, Christopher R.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 16.12.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/1; 13/106; 13/21; 13/31; 14/19; 14/28; 14/34; 14/35; 14/63; 147/135; 147/28; 38; 631/250/262; 692/308/153; 82/29; 82/51; 82/58; Animal models; Animals; Antidotes; Biocompatibility; Chromatin; Cytotoxicity; Damage; Deoxyribonucleic acid; DNA; Erythrocytes; Erythrocytes - drug effects; Erythrocytes - pathology; Extracellular Traps - drug effects; Female; Heart; Histones; Histones - metabolism; Histones - toxicity; Humanities and Social Sciences; Humans; In vivo methods and tests; Ischemia; Lipid Bilayers; Lipids; Male; Mice, Inbred BALB C; Mice, Inbred C57BL; multidisciplinary; Myocardial Infarction - blood; Neutralizing; Pathological effects; Phenotypes; Platelet Activation - drug effects; Polyanions; Polyelectrolytes; Polymers - chemistry; Polymers - pharmacology; Rats, Wistar; Reperfusion; Reperfusion Injury - blood; Reperfusion Injury - pathology; Science; Science (multidisciplinary); Sepsis; Sepsis - blood; Sepsis - drug therapy; Sepsis - pathology; Thromboembolism; Thrombosis
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20231-y

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. Histones, proteins that bind DNA, are toxic for pathogens outside cells but can also cause multi-organ damage as seen in sepsis. Here the authors develop small negatively charged molecules that can be used as histone antidotes, and show that they improve the phenotype in mouse models with histone-related pathologies.