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

Qiufang Deng(Xiangya Hospital Central South University), Baihong Pan(Central South University), Hasan B. Alam(University of Michigan–Ann Arbor), Yingjian Liang(First Hospital of China Medical University), Zhenyu Wu(Central South University), Baoling Liu(University of Michigan–Ann Arbor), Nirit Mor‐Vaknin(University of Michigan–Ann Arbor), Xiuzhen Duan(Loyola University Medical Center), Aaron M. Williams(University of Michigan–Ann Arbor), Yuzi Tian(Central South University), Justin Zhang(University of Michigan–Ann Arbor), Yongqing Li(University of Michigan–Ann Arbor)
Frontiers in Immunology
January 8, 2020
10.3389/fimmu.2019.02957
Cited by 102Open Access
Full Text

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.

Related Papers

Extracellular DNA traps promote thrombosis
Tobias A. Fuchs, Alexander Brill, Daniel Duerschmied et al.|Proceedings of the National Academy of Sciences|2010|2.4k
Extracellular histones are major mediators of death in sepsis
Jun Xu, Xiaomei Zhang, Rosana Pelayo et al.|Nature Medicine|2009|1.5k
Neutrophil Extracellular Traps: Double-Edged Swords of Innate Immunity
Mariana J. Kaplan, Marko Radic|The Journal of Immunology|2012|1.2k
Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms
Constantin F. Urban, Ulrike Reichard, Volker Brinkmann et al.|Cellular Microbiology|2005|994
Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4
Fabrizio Semeraro, Concetta T. Ammollo, James H. Morrissey et al.|Blood|2011|836