Annexin A2 Modulates ROS and Impacts Inflammatory Response via IL-17 Signaling in Polymicrobial Sepsis Mice

PLoS Pathogens

Xuefeng Li¹  Lingyun Sun¹  Lizhu Fang¹  Yongsheng Wang¹  Min Wu²  Rongpeng Li³  Sisi He³ 

[1] Department of Biomedical Sciences, University of North Dakota, Grand Forks, North Dakota, United States of America;Department of Rheumatology and Immunology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, P. R. China;State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan, P. R. China

关键词: Sepsis;    Neutrophils;    Peritoneal lavage;    Inflammation;    Mouse models;    Colon;    Cytokines;    Inflammatory diseases;   

DOI  :  10.1371/journal.ppat.1005743

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Sepsis is a progressive disease manifesting excessive inflammatory responses, severe tissue injury, organ dysfunction, and, ultimately, mortality. Since currently, there are limited therapeutic options for this disease, further understanding the molecular pathogenesis of sepsis may help develop effective treatments. Here we identify a novel role for Annexin A2 (AnxA2), a multi-compartmental protein, in inhibiting pro-inflammatory response by regulating reactive oxygen species (ROS) and IL-17 signaling during sepsis. In cecal ligation and puncture (CLP) sepsis models, anxa2-/- mice manifested increased pro-inflammatory cytokines and neutrophil infiltration, but decreased bacterial clearance and animal survival. In addition, AnxA2 deficiency led to intensified ROS and IL-17A. Using site directed mutagenesis, we uncovered that cysteine 9 of AnxA2 was the most important aa (site) for regulation of ROS levels. Furthermore, ROS appears to be responsible for elevated IL-17A levels and subsequently exaggerated inflammatory response. Depletion of IL-17 via CRISPR/Cas9 KO strategy down-regulated inflammation and conferred protection against sepsis in anxa2-/- mice. Our findings reveal a previously undemonstrated function for AnxA2 in inflammatory response in polymicrobial sepsis models via an AnxA2-ROS-IL-17 axis, providing insight into the regulation of pathophysiology of sepsis.

【 授权许可】

CC BY