title: Annexin A5 increases survival in murine sepsis model by inhibiting HMGB1-mediated pro-inflammation and coagulation.
abstract: The identification of HMGB1 as a late-mediator in sepsis has highlighted HMGB1 as a promising therapeutic target for sepsis treatment. Recent studies have revealed that annexin A5, a 35 kDa Ca2+-dependent phospholipid binding protein, exerts anti-inflammatory effect by inhibiting LPS binding to TLR4/MD2 complex. Annexin A5 administration has been shown to protect against endotoxin lethality even when the treatment was given after the early cytokine response, which prompted our group to suspect that annexin A5 may inhibit the binding of HMGB1, as well as endotoxin to TLR4. Here we suggest annexin A5 as a new inhibitor of HMGB1-mediated pro-inflammatory cytokine production and coagulation in sepsis. We first confirmed the inhibitory role of annexin A5 in LPS-induced production of pro-inflammatory cytokines bothin vitroandin vivo. We observed that annexin A5 protects against tissue damage and organ dysfunction during endotoxemiain vivo. We then assessed the inhibiting role of annexin A5 in HMGB1/TLR4 interaction, and showed that annexin A5 treatment reduces HMGB1-mediated cytokines IL6 and TNFα bothin vitroandin vivo. Finally, we confirmed that anticoagulant property of annexin A5 persists in various septic conditions including elevated HMGB1. Overall, we suggest annexin A5 as an alternative therapeutic approach for controlling HMGB1-mediated pro-inflammation and coagulation in patients with sepsis.
authors.affiliation: Department of Immunology, KU open innovation center and School of Medicine, Konkuk University, Chungju 380-701, South Korea.
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Dental Hygiene, Hanseo University, Seosan 356-706, South Korea.
authors.forename: Jong-Hwa
authors.initials: JH
authors.lastname: Jang
authors.affiliation: Department of Immunology, KU open innovation center and School of Medicine, Konkuk University, Chungju 380-701, South Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Choi
authors.affiliation: Department of Immunology, KU open innovation center and School of Medicine, Konkuk University, Chungju 380-701, South Korea.
authors.forename: Young Seob
authors.initials: YS
authors.lastname: Kim
authors.affiliation: Department of Immunology, KU open innovation center and School of Medicine, Konkuk University, Chungju 380-701, South Korea.
authors.forename: Eun Ji
authors.initials: EJ
authors.lastname: Lee
authors.affiliation: Department of Immunology, KU open innovation center and School of Medicine, Konkuk University, Chungju 380-701, South Korea.
authors.forename: In Duk
authors.initials: ID
authors.lastname: Jung
authors.affiliation: Department of Immunology, KU open innovation center and School of Medicine, Konkuk University, Chungju 380-701, South Korea.
authors.forename: Hee Dong
authors.initials: HD
authors.lastname: Han
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.|Departments of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.|Departments of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.|Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.|Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, United States.
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.affiliation: Department of Immunology, KU open innovation center and School of Medicine, Konkuk University, Chungju 380-701, South Korea.
authors.forename: Tae Heung
authors.initials: TH
authors.lastname: Kang
authors.affiliation: Department of Immunology, KU open innovation center and School of Medicine, Konkuk University, Chungju 380-701, South Korea.
authors.forename: Yeong-Min
authors.initials: YM
authors.lastname: Park
keywords: HMGB1 Protein; Toll-like receptor 4; anticoagulants; lipopolysaccharides; severe sepsis