Abstract
The pathogen- and damage-associated molecular patterns (for example, bacterial endotoxin and adenosine 5'-triphosphate [ATP]) activate the double-stranded RNA-activated protein kinase R (PKR) to trigger the inflammasome-dependent high mobility group box 1 (HMGB1) release. Extracellular ATP contributes to the inflammasome activation through binding to the plasma membrane purinergic P2X7 receptor (P2X7R), triggering the opening of P2X7R channels and the pannexin-1 (panx-1) hemichannels permeable for larger molecules up to 900 daltons. It was previously unknown whether panx-1 channel blockers can abrogate lipopolysaccharide (LPS)-induced PKR activation and HMGB1 release in innate immune cells. Here we demonstrated that a major gancao (licorice) component (glycyrrhizin, or glycyrrhizic acid) derivative, carbenoxolone (CBX), dose dependently abrogated LPS-induced HMGB1 release in macrophage cultures with an estimated IC50 ≈ 5 μmol/L. In an animal model of polymicrobial sepsis (induced by cecal ligation and puncture [CLP]), repetitive CBX administration beginning 24 h after CLP led to a significant reduction of circulating and peritoneal HMGB1 levels, and promoted a significant increase in animal survival rates. As did P2X7R antagonists (for example, oxidized ATP, oATP), CBX also effectively attenuated LPS-induced P2X7R/panx-1 channel activation (as judged by Lucifer Yellow dye uptake) and PKR phosphorylation in primary peritoneal macrophages. Collectively, these results suggested that CBX blocks LPS-induced HMGB1 release possibly through impairing PKR activation, supporting the involvement of PKR in the regulation of HMGB1 release.
Highlights
Sepsis is an overwhelming systemic inflammatory response to severe infections, and remains the primary cause of mortality in medical intensive care units
We demonstrated that CBX remarkably inhibited endotoxin-induced high mobility group box 1 (HMGB1) release possibly through blocking P2X7 receptor (P2X7R)-gated panx-1 channels, and rescued mice from lethal sepsis
In light of the pathogenic role of HMGB1 in lethal sepsis [8], we explored the therapeutic potential of CBX using a clinically relevant animal model of polymicrobial sepsis induced by cecal ligation and puncture (CLP)
Summary
Sepsis is an overwhelming systemic inflammatory response to severe infections, and remains the primary cause of mortality in medical intensive care units. It afflicts approximately 750,000 Americans each year, and costs the United States healthcare system nearly $17 billion annually [1]. HMGB1neutralizing antibodies confer protection against lethal endotoxemia [6] and sepsis [8,10] even when given 24 hours after the onset of sepsis, establishing HMGB1 as a late mediator of lethal inflammatory diseases [11]
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