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Increased release of sMD-2 during human endotoxemia and sepsis: a role for endothelial cells
Tim G A M Wolfs1, Irène Dunn-Siegrist, Cornelis van't Veer
1Department of Surgery, Nutrition and Toxicology Research Institute Maastricht, Academic Hospital Maastricht and Maastricht University, Universiteitssingel 50, 6200 MD Maastricht, The Netherlands.
Abstract:
MD-2 is the crucial cofactor of TLR4 in the detection of LPS. Here, we show that soluble MD-2 (sMD-2) circulates in plasma of healthy individuals as a polymeric protein. The total amount of sMD-2 in septic plasma was strongly elevated and contained both sMD-2 polymers and monomers, the latter representing the putative biologically active form of MD-2. Moreover, during experimental human endotoxemia, the monomeric and total sMD-2 content in plasma increased with the kinetics of an acute phase protein. The increase in sMD-2 monomers was paralleled by enhanced TLR4 costimulatory activity. The presence of functional sMD-2 during endotoxemia and sepsis was confirmed by immunodepletion. Immunohistochemistry revealed that MD-2 expression in septic patients was strongly enhanced on endothelium and multiple inflammatory cells in lung and liver. In vitro studies showed that sMD-2 release appears to be restricted to endothelial cells and dendritic cells. Release of sMD-2 by endothelial cells was strongly enhanced by LPS and TNF-alpha stimulation. Taken together, this study demonstrates the increase of both circulating polymeric and functional monomeric sMD-2 during endotoxemia and sepsis, and evidence is provided that the endothelium is involved in this process.
Insights
Soluble MD-2 (sMD-2), a key partner for Toll-like receptor 4 (TLR4), increases in sepsis and endotoxemia. This study shows sMD-2 monomers are the active form, released by endothelial cells, enhancing immune responses.
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- MD-2 is essential for Toll-like receptor 4 (TLR4) to detect lipopolysaccharide (LPS).
- Soluble MD-2 (sMD-2) exists in plasma, but its role in sepsis and endotoxemia is not fully understood.
Purpose of the Study:
- To investigate the forms and function of circulating sMD-2 during endotoxemia and sepsis.
- To identify the cellular sources and regulation of sMD-2 release.
- To assess the contribution of sMD-2 to TLR4-mediated immune responses.
Main Methods:
- Quantification of sMD-2 polymers and monomers in plasma from healthy individuals, endotoxemic, and septic patients.
- Assessment of TLR4 costimulatory activity.
- Immunodepletion assays to confirm functional sMD-2 presence.
- Immunohistochemistry to determine MD-2 expression in tissues.
- In vitro studies on sMD-2 release from endothelial and dendritic cells stimulated with LPS and TNF-alpha.
Main Results:
- sMD-2 circulates as polymers in healthy individuals; septic plasma contains elevated polymers and monomers.
- Monomeric sMD-2, the putative active form, increases during endotoxemia and sepsis, paralleling enhanced TLR4 activity.
- MD-2 expression is upregulated on endothelial and inflammatory cells in septic patients.
- Endothelial cells and dendritic cells are primary sources of sMD-2 release, with LPS and TNF-alpha enhancing release from endothelial cells.
Conclusions:
- Circulating monomeric sMD-2 is a functional form that increases during endotoxemia and sepsis.
- Endothelial cells play a significant role in releasing sMD-2, particularly upon inflammatory stimulation.
- sMD-2 is an acute phase protein involved in TLR4-mediated immune responses during infection.
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