Citrullinated Histone H3 as a Therapeutic Target for Endotoxic Shock in Mice

Qiufang Deng, Baihong Pan, Hasan B. Alam*, Yingjian Liang, Zhenyu Wu, Baoling Liu, Nirit Mor-Vaknin, Xiuzhen Duan, Aaron M. Williams, Yuzi Tian, Justin Zhang, Yongqing Li

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

Abstract

Sepsis results in millions of deaths every year, with acute lung injury (ALI) being one of the leading causes of mortality in septic patients. As neutrophil extracellular traps (NETs) are abundant in sepsis, neutralizing components of NETs may be a useful strategy to improve outcomes of sepsis. Citrullinated histone H3 (CitH3) has been recently shown to be involved in the NET formation. In this study, we demonstrate that CitH3 damages human umbilical vein endothelial cells (HUVECs) and potentiates NET formation through a positive feedback mechanism. We developed a novel CitH3 monoclonal antibody to target peptidylarginine deiminase (PAD) 2 and PAD 4 generated CitH3. In a mouse model of lethal lipopolysaccharide (LPS) induced shock, neutralizing CitH3 with the newly developed anti-CitH3 monoclonal antibody attenuates inflammatory responses, ameliorates ALI, and improves survival. Our study suggests that effectively blocking circulating CitH3 might be a potential therapeutic method for the treatment of endotoxemia.

Original languageEnglish (US)
Article number2957
JournalFrontiers in immunology
Volume10
DOIs
StatePublished - Jan 9 2020
Externally publishedYes

Keywords

  • acute lung injury
  • citrullinated histone H3
  • endotoxic shock
  • inflammation
  • neutrophil extracellular traps
  • new anti-CitH3 antibody
  • survival

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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