Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock.

Abstract

To identify new components that regulate the inflammatory cascade during sepsis, we characterized the functions of myeloid-related protein-8 (Mrp8, S100A8) and myeloid-related protein-14 (Mrp14, S100A9), two abundant cytoplasmic proteins of phagocytes. We now demonstrate that mice lacking Mrp8-Mrp14 complexes are protected from endotoxin-induced lethal shock and Escherichia coli-induced abdominal sepsis. Both proteins are released during activation of phagocytes, and Mrp8-Mrp14 complexes amplify the endotoxin-triggered inflammatory responses of phagocytes. Mrp8 is the active component that induces intracellular translocation of myeloid differentiation primary response protein 88 and activation of interleukin-1 receptor-associated kinase-1 and nuclear factor-kappaB, resulting in elevated expression of tumor necrosis factor-alpha (TNF-alpha). Using phagocytes expressing a nonfunctional Toll-like receptor 4 (TLR4), HEK293 cells transfected with TLR4, CD14 and MD2, and by surface plasmon resonance studies in vitro, we demonstrate that Mrp8 specifically interacts with the TLR4-MD2 complex, thus representing an endogenous ligand of TLR4. Therefore Mrp8-Mrp14 complexes are new inflammatory components that amplify phagocyte activation during sepsis upstream of TNFalpha-dependent effects.

• Authors: Thomas Vogl, Klaus Tenbrock, Stephan Ludwig, Nadja Leukert, Christina Ehrhardt, Marieke A D van Zoelen, Wolfgang Nacken, Dirk Foell, Tom van der Poll, Clemens Sorg, Johannes Roth
• Journal: Nature medicine (Nat Med) Vol. 13 Issue 9 Pg. 1042-9 (Sep 2007) ISSN: 1078-8956 [Print] United States
• PMID: 17767165 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Calgranulin A
• Calgranulin B
• Endotoxins
• Ligands
• Lipopolysaccharides
• Tlr4 protein, mouse
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha

Topics

• Animals
• Calgranulin A (deficiency, physiology)
• Calgranulin B (genetics, physiology)
• Cell Line, Tumor
• Cells, Cultured
• Endotoxins (toxicity)
• Flow Cytometry
• Humans
• Ligands
• Lipopolysaccharides (toxicity)
• Mice
• Mice, Knockout
• Oligonucleotide Array Sequence Analysis
• Pulmonary Alveoli (cytology, physiology)
• Shock, Septic (genetics, physiopathology)
• Toll-Like Receptor 4 (physiology)
• Tumor Necrosis Factor-alpha (genetics)