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.
Highlights
Sepsis is a life-threatening clinicalsyndrome resulting from the excessive proinflammatory cytokine response to infection combined with coagulopathy
Since the cytokine storm can induce tissue damage and multi-organ failure [8], we examined the effect of annexin A5 treatment on LPS-induced organ damage by assessing serum concentrations of aspartate transaminase (AST), alanine transaminase (ALT) and blood urea nitrogen (BUN)
Rand et al first found that annexin A5 reduces LPS-induced TNF-α production [28]. Arnold et al showed that annexin A5 decreases myocardial TNF-α expression by inhibition of LPS binding toll-like receptor 4 (TLR4)/MD2 complex, improving cardiac function and survival during endotoxemia [5]
Summary
syndrome resulting from the excessive proinflammatory cytokine response to infection combined with coagulopathy. The toll-like receptor 4 (TLR4) expressed on dendritic cells is responsible for detecting the presence of lipopolysaccharides (LPS), a cell wall component in gram-negative bacteria [5]. TLR4 signaling promotes the gene expression of proinflammatory cytokines, such as TNF-α and IL-6, within minutes after LPS exposure [4,6,7]. Excessive production of these cytokines by immune cells results in cytokine storm, which induces tissue damage and organ dysfunction, the consequence of which is called severe sepsis [8]
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