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

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

doi:10.3389/fimmu.2019.02957

Frontiers in Immunology (Jan 2020)

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

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

Affiliations

Qiufang Deng: Xiangya Hospital, Central South University, Changsha, China
Qiufang Deng: Department of Surgery, University of Michigan, Ann Arbor, MI, United States
Baihong Pan: Xiangya Hospital, Central South University, Changsha, China
Baihong Pan: Department of Surgery, University of Michigan, Ann Arbor, MI, United States
Hasan B. Alam: Department of Surgery, University of Michigan, Ann Arbor, MI, United States
Yingjian Liang: Department of Surgery, University of Michigan, Ann Arbor, MI, United States
Yingjian Liang: The First Hospital, China Medical University, Shenyang, China
Zhenyu Wu: Xiangya Hospital, Central South University, Changsha, China
Zhenyu Wu: Department of Surgery, University of Michigan, Ann Arbor, MI, United States
Baoling Liu: Department of Surgery, University of Michigan, Ann Arbor, MI, United States
Nirit Mor-Vaknin: Division of Infectious Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, United States
Xiuzhen Duan: Department of Pathology, Loyola University Medical Center, Maywood, IL, United States
Aaron M. Williams: Department of Surgery, University of Michigan, Ann Arbor, MI, United States
Yuzi Tian: Xiangya Hospital, Central South University, Changsha, China
Yuzi Tian: Department of Surgery, University of Michigan, Ann Arbor, MI, United States
Justin Zhang: Department of Surgery, University of Michigan, Ann Arbor, MI, United States
Yongqing Li: Department of Surgery, University of Michigan, Ann Arbor, MI, United States

DOI: https://doi.org/10.3389/fimmu.2019.02957
Journal volume & issue: Vol. 10

Abstract

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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.

Published in Frontiers in Immunology

ISSN: 1664-3224 (Online)
Publisher: Frontiers Media S.A.
Country of publisher: Switzerland
LCC subjects: Medicine: Internal medicine: Specialties of internal medicine: Immunologic diseases. Allergy
Website: http://journal.frontiersin.org/journal/immunology

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