Annexin A5 increases survival in murine sepsis model by inhibiting HMGB1-mediated pro-inflammation and coagulation
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Updated: Mar 17, 2026
Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies
Published on: April 11, 2012
Jung Hwa Park1, Jong-Hwa Jang2, Eun Jung Choi1
1Department of Immunology, KU open innovation center and School of Medicine, Konkuk University, Chungju 380-701, South Korea.
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 both in vitro and in vivo. We observed that annexin A5 protects against tissue damage and organ dysfunction during endotoxemia in 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 both in vitro and in 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.
Insights
Annexin A5 inhibits high-mobility group box 1 (HMGB1) and lipopolysaccharide (LPS) inflammatory responses in sepsis. This study suggests annexin A5 as a potential therapeutic for sepsis by reducing HMGB1-mediated inflammation and coagulation.
Area of Science:
- Immunology
- Biochemistry
- Pharmacology
Background:
- High-mobility group box 1 (HMGB1) is identified as a key late-stage mediator in sepsis.
- Annexin A5 inhibits lipopolysaccharide (LPS) binding to Toll-like receptor 4 (TLR4)/MD2 complex, demonstrating anti-inflammatory properties.
- Annexin A5's protective effects against endotoxin lethality suggest potential inhibition of HMGB1-TLR4 interactions.
Purpose of the Study:
- To investigate annexin A5 as an inhibitor of HMGB1-mediated pro-inflammatory cytokine production and coagulation in sepsis.
- To evaluate the therapeutic potential of annexin A5 in sepsis models.
Main Methods:
- In vitro and in vivo experiments were conducted to assess annexin A5's effects on LPS-induced cytokine production.
- HMGB1/TLR4 interaction inhibition by annexin A5 was evaluated.
- Annexin A5's anticoagulant properties were assessed under septic conditions.
Main Results:
- Annexin A5 confirmed inhibitory effects on LPS-induced pro-inflammatory cytokine production both in vitro and in vivo.
- Annexin A5 administration protected against tissue damage and organ dysfunction in endotoxemia models.
- Annexin A5 was shown to reduce HMGB1-mediated IL-6 and TNF-α production and maintain anticoagulant properties in septic conditions.
Conclusions:
- Annexin A5 effectively inhibits HMGB1-mediated pro-inflammatory cytokine production and coagulation in sepsis.
- Annexin A5 demonstrates protective effects against sepsis-induced tissue damage and organ dysfunction.
- Annexin A5 presents a promising alternative therapeutic strategy for managing sepsis by targeting HMGB1 pathways.
