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Published on: December 9, 2022
Expression and role of myeloid-related protein-14 in clinical and experimental sepsis
Marieke A D van Zoelen1, Thomas Vogl, Dirk Foell
1Center for Infection and Immunity Amsterdam, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. M.A.D.vanZoelen@umcutrecht.nl
Rationale:
Myeloid-related protein-8 (MRP8) and MRP14 can form heterodimers that elicit a variety of inflammatory responses. We showed that MRP8/14 is a ligand for Toll-like receptor-4, and that mice deficient in MRP8/14 are protected against endotoxic shock-induced lethality.
Objectives:
To determine (1) the extent of MRP8/14 release in patients with sepsis and/or peritonitis and in healthy humans exposed to LPS and (2) the contribution of MRP8/14 to the host response in murine abdominal sepsis.
Methods:
MRP8/14 was measured in 51 patients with severe sepsis, 8 subjects after intravenous injection of LPS, and 17 patients with peritonitis. Host responses to sepsis were compared in mrp14 gene-deficient (and thereby MRP8/14-deficient) and wild-type mice intraperitoneally injected with Escherichia coli.
Measurements And Main Results:
Patients with sepsis displayed elevated circulating MRP8/14 concentrations on both Days 0 and 3, and LPS injection resulted in systemic MRP8/14 release in healthy humans. In patients with peritonitis, MRP8/14 levels in abdominal fluid were more than 15-fold higher than in plasma. MRP14-deficient mice displayed improved defense against E. coli abdominal sepsis in an early phase, as indicated by diminished dissemination of the bacteria at 6 hours. In addition, MRP14-deficient mice demonstrated decreased systemic inflammation, as reflected by lower cytokine plasma concentrations, and less severe liver damage.
Conclusions:
Human sepsis and endotoxemia are associated with enhanced release of MRP8/14. In abdominal sepsis, MRP8/14 likely occurs primarily at the site of the infection, facilitating bacterial dissemination at an early phase and liver injury.
Insights
Myeloid-related protein-8/14 (MRP8/14) is released during human sepsis and endotoxemia. MRP8/14 deficiency improves early defense against abdominal sepsis in mice, reducing bacterial spread and liver damage.
Area of Science:
- Immunology
- Infectious Disease
- Molecular Biology
Background:
- Myeloid-related protein-8 (MRP8) and MRP14 form heterodimers involved in inflammatory responses.
- MRP8/14 acts as a ligand for Toll-like receptor-4.
- MRP8/14-deficient mice show protection against endotoxic shock.
Purpose of the Study:
- Quantify MRP8/14 release in sepsis, peritonitis, and LPS-exposed humans.
- Assess MRP8/14's role in host response during murine abdominal sepsis.
Main Methods:
- MRP8/14 levels measured in sepsis, peritonitis patients, and LPS-exposed healthy subjects.
- Compared sepsis response in MRP14-deficient and wild-type mice challenged with E. coli.
Main Results:
- Elevated MRP8/14 in sepsis patients; systemic release after LPS exposure.
- MRP8/14 levels 15-fold higher in abdominal fluid vs. plasma in peritonitis.
- MRP14-deficient mice showed reduced bacterial dissemination, lower cytokine levels, and less liver damage.
Conclusions:
- Sepsis and endotoxemia increase MRP8/14 release in humans.
- MRP8/14 contributes to early bacterial dissemination and liver injury in abdominal sepsis.
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