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

Nat Med. 2007 Sep;13(9):1042-9. doi: 10.1038/nm1638. Epub 2007 Sep 2.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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