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 von Itzstein; Christopher R. Parish

doi:10.1038/s41467-020-20231-y

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. StephensMark von Itzstein, Christopher R. Parish^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

57 Citations (Scopus)

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.

Original language	English
Article number	6408
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20231-y
Publication status	Published - Dec 2020

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Meara, C. H. O., Coupland, L. A., Kordbacheh, F., Quah, B. J. C., Chang, C. W., Simon Davis, D. A., Bezos, A., Browne, A. M., Freeman, C., Hammill, D. J., Chopra, P., Pipa, G., Madge, P. D., Gallant, E., Segovis, C., Dulhunty, A. F., Arnolda, L. F., Mitchell, I., Khachigian, L. M., ... Parish, C. R. (2020). Neutralizing the pathological effects of extracellular histones with small polyanions. Nature Communications, 11(1), Article 6408. https://doi.org/10.1038/s41467-020-20231-y

@article{5a5cda358f304acbbb2488daeadd8d64,

title = "Neutralizing the pathological effects of extracellular histones with small polyanions",

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.",

author = "Meara, {Connor H.O{\textquoteright}} and Coupland, {Lucy A.} and Farzaneh Kordbacheh and Quah, {Benjamin J.C.} and Chang, {Chih Wei} and {Simon Davis}, {David A.} and Anna Bezos and Browne, {Anna M.} and Craig Freeman and Hammill, {Dillon J.} and Pradeep Chopra and Gergely Pipa and Madge, {Paul D.} and Esther Gallant and Courtney Segovis and Dulhunty, {Angela F.} and Arnolda, {Leonard F.} and Imogen Mitchell and Khachigian, {Levon M.} and Stephens, {Ross W.} and {von Itzstein}, Mark and Parish, {Christopher R.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = dec,

doi = "10.1038/s41467-020-20231-y",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

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Meara, CHO, Coupland, LA, Kordbacheh, F, Quah, BJC, Chang, CW, Simon Davis, DA , Bezos, A, Browne, AM, Freeman, C, Hammill, DJ, Chopra, P, Pipa, G, Madge, PD, Gallant, E, Segovis, C, Dulhunty, AF, Arnolda, LF, Mitchell, I, Khachigian, LM, Stephens, RW, von Itzstein, M & Parish, CR 2020, 'Neutralizing the pathological effects of extracellular histones with small polyanions', Nature Communications, vol. 11, no. 1, 6408. https://doi.org/10.1038/s41467-020-20231-y

TY - JOUR

T1 - Neutralizing the pathological effects of extracellular histones with small polyanions

AU - Meara, Connor H.O’

AU - Coupland, Lucy A.

AU - Kordbacheh, Farzaneh

AU - Quah, Benjamin J.C.

AU - Chang, Chih Wei

AU - Simon Davis, David A.

AU - Bezos, Anna

AU - Browne, Anna M.

AU - Freeman, Craig

AU - Hammill, Dillon J.

AU - Chopra, Pradeep

AU - Pipa, Gergely

AU - Madge, Paul D.

AU - Gallant, Esther

AU - Segovis, Courtney

AU - Dulhunty, Angela F.

AU - Arnolda, Leonard F.

AU - Mitchell, Imogen

AU - Khachigian, Levon M.

AU - Stephens, Ross W.

AU - von Itzstein, Mark

AU - Parish, Christopher R.

PY - 2020/12

Y1 - 2020/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85097606404&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-20231-y

DO - 10.1038/s41467-020-20231-y

M3 - Article

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6408

ER -

Neutralizing the pathological effects of extracellular histones with small polyanions

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