Mrp8 and Mrp14 are endogenous activators of Toll-like receptor 4, promoting lethal, endotoxin-induced shock.
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.
Vogl
Thomas
T
Institute of Experimental Dermatology, University of Münster, D-48129 Münster, Germany.
Tenbrock
Klaus
K
Ludwig
Stephan
S
Leukert
Nadja
N
Ehrhardt
Christina
C
van Zoelen
Marieke A D
MA
Nacken
Wolfgang
W
Foell
Dirk
D
van der Poll
Tom
T
Sorg
Clemens
C
Roth
Johannes
J
D000818:Animals; D040501:Calgranulin A / Q000172:deficiency / Q000502:physiology*; D040502:Calgranulin B / Q000235:genetics / Q000502:physiology*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004731:Endotoxins / Q000633:toxicity*; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011650:Pulmonary Alveoli / Q000166:cytology / Q000502:physiology; D012772:Shock, Septic / Q000235:genetics / Q000503:physiopathology*; D051197:Toll-Like Receptor 4 / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D040501:Calgranulin A; D040502:Calgranulin B; D004731:Endotoxins; D008024:Ligands; D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha