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Toll-like receptor 4 (TLR4) antagonist eritoran tetrasodium attenuates liver ischemia and reperfusion injury through inhibition of high-mobility group box protein B1 (HMGB1) signaling.

ABSTRACT: Toll-like receptor 4 (TLR4) is ubiquitously expressed on parenchymal and immune cells of the liver and is the most studied TLR responsible for the activation of proinflammatory signaling cascades in liver ischemia and reperfusion (I/R). Since pharmacological inhibition of TLR4 during the sterile inflammatory response of I/R has not been studied, we sought to determine whether eritoran, a TLR4 antagonist trialed in sepsis, could block hepatic TLR4-mediated inflammation and end organ damage. When C57BL/6 mice were pretreated with eritoran and subjected to warm liver I/R, there was significantly less hepatocellular injury compared to control counterparts. Additionally, we found that eritoran is protective in liver I/R through inhibition of high-mobility group box protein B1 (HMGB1)-mediated inflammatory signaling. When eritoran was administered in conjunction with recombinant HMGB1 during liver I/R, there was significantly less injury, suggesting that eritoran blocks the HMGB1-TLR4 interaction. Not only does eritoran attenuate TLR4-dependent HMGB1 release in vivo, but this TLR4 antagonist also dampened HMGB1's release from hypoxic hepatocytes in vitro and thereby weakened HMGB1's activation of innate immune cells. HMGB1 signaling through TLR4 makes an important contribution to the inflammatory response seen after liver I/R. This study demonstrates that novel blockade of HMGB1 by the TLR4 antagonist eritoran leads to the amelioration of liver injury.

SUBMITTER: Mcdonald KA

PROVIDER: S-EPMC4365061 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Toll-like receptor 4 (TLR4) antagonist eritoran tetrasodium attenuates liver ischemia and reperfusion injury through inhibition of high-mobility group box protein B1 (HMGB1) signaling.

Mcdonald Kerry-Ann KA Huang Hai H Tohme Samer S Loughran Patricia P Ferrero Kimberly K Billiar Timothy T Tsung Allan A

Molecular medicine (Cambridge, Mass.) 20150313

Toll-like receptor 4 (TLR4) is ubiquitously expressed on parenchymal and immune cells of the liver and is the most studied TLR responsible for the activation of proinflammatory signaling cascades in liver ischemia and reperfusion (I/R). Since pharmacological inhibition of TLR4 during the sterile inflammatory response of I/R has not been studied, we sought to determine whether eritoran, a TLR4 antagonist trialed in sepsis, could block hepatic TLR4-mediated inflammation and end organ damage. When ...[more]

PMID: 25375408

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Project description:The 2013-2016 outbreak of Ebola virus (EBOV) in West Africa, which has seen intermittent reemergence since it was officially declared over in February of 2016, has demonstrated the need for the rapid development of therapeutic intervention strategies. Indirect evidence has suggested that the EBOV infection shares several commonalities associated with the onset of bacterial sepsis, including the development of a "cytokine storm." Eritoran, a Toll-like receptor 4 (TLR4) antagonist, was previously shown to result in protection of mice against lethal influenza virus infection. Here, we report that eritoran protects against the lethality caused by EBOV and the closely related Marburg virus (MARV) in mice. Daily administration of eritoran reduced clinical signs of the disease and, unexpectedly, resulted in reduced viral titers. Analysis of peripheral blood indicated that eritoran reduced granulocytosis despite an apparent increase in the percentage of activated neutrophils. Surprisingly, the increased survival rate and reduced viremia were not accompanied by increased CD3+ T lymphocytes, as lymphopenia was more pronounced in eritoran-treated mice. Overall, a global reduction in the levels of multiple cytokines, chemokines, and free radicals was detected in serum, suggesting that eritoran treatment may alleviate the severity of the "cytokine storm." Last, we provide compelling preliminary evidence suggesting that eritoran treatment may alter the kinetics of cytokine responses. Hence, these studies are the first to demonstrate the role of TLR4 in the pathogenesis of EBOV disease and indicate that eritoran is a prime candidate for further evaluation as a clinically viable therapeutic intervention strategy for EBOV and MARV infections.IMPORTANCE A hallmark of bacterial sepsis is the uncontrolled activation of the TLR4 pathway, which is the primary cause of the pathological features associated with this disease. Considering the importance of TLR4 signaling in bacterial sepsis and the remarkable pathological similarities associated with infections caused by filoviruses Ebola virus (EBOV) and Marburg virus (MARV), we assessed the ability of eritoran, a TLR4 antagonist, to protect mice against these viruses. Here, we show that eritoran effectively promotes survival of mice of filovirus infection, as 70% and 90% of mice receiving daily eritoran treatment survived lethal EBOV and MARV infections, respectively. Eritoran treatment resulted in a remarkable global reduction of inflammatory mediators, which is suggestive of the mechanism of action of this therapeutic treatment. These studies are the first to show the critical importance of the TLR4 pathway in the pathogenesis of filovirus infection and may provide a new avenue for therapeutic interventions.

Dataset Information

Toll-like receptor 4 (TLR4) antagonist eritoran tetrasodium attenuates liver ischemia and reperfusion injury through inhibition of high-mobility group box protein B1 (HMGB1) signaling.

Publications

Toll-like receptor 4 (TLR4) antagonist eritoran tetrasodium attenuates liver ischemia and reperfusion injury through inhibition of high-mobility group box protein B1 (HMGB1) signaling.

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