Cited by 1,418Immune Response and InflammationS100 Proteins and AnnexinsSepsis Diagnosis and Treatment

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

Vogl, Thomas, Tenbrock, Klaus, Ludwig, Stephan, Leukert, Nadja, Ehrhardt, Christina, van Zoelen, Marieke A D, Nacken, Wolfgang, Foell, Dirk +3 more·2007·Nature Medicine

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.

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Crossref · 10.1038/nm1638

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  • S100A8/9 bind to TLR4 and RAGE, which activate diverse signaling cascades.

    “S100A8/9 bind to Toll-like receptor 4 (TLR4) and RAGE (receptor for advanced glycation end products), which activate diverse signaling cascades (Gebhardt et al., 2006; Vogl et al., 2007).”

    From A CXCL1 Paracrine Network Links Cancer Chemoresistance and Metastasis (2012) · cites this paper as Vogl et al., 2007

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Authors
Vogl, T., Tenbrock, K., Ludwig, S., Leukert, N., Ehrhardt, C., van Zoelen, M. A. D., Nacken, W., Foell, D., van der Poll, T., Sorg, C., & Roth, J.
Affiliations
University of Münster (DE)
Corresponding author
Roth, Johannes
Venue
Nature Medicine
Published
2007-09
Volume
13
Issue
9
Pages
1042-1049
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
OpenAlex
W2097599737
Cited by
1,418
References
47
Citations by year
2026: 61 · 2025: 52 · 2024: 80 · 2023: 86 · 2022: 79 · 2021: 83 · 2020: 77 · 2019: 74 · 2018: 70 · 2017: 92 · 2016: 92 · 2015: 92 · 2014: 73 · 2013: 104 · 2012: 75
FWCI
19.12
Type
journal article
Language
en
Open access
closed
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › S100 Proteins and Annexins
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
Keywords
S100A8, S100A9, TLR4, endotoxic shock, sepsis, endogenous ligands, phagocyte activation, MD-2, CD14, MyD88, TRAF6, NF-κB, TNF-α, Escherichia coli, inflammation
MeSH terms
Animals, Cells, Cultured, Endotoxins, Flow Cytometry, Humans, Ligands, Lipopolysaccharides, Pulmonary Alveoli, Shock, Septic, Tumor Necrosis Factor-alpha, Mice, Knockout, Oligonucleotide Array Sequence Analysis, Calgranulin A, Calgranulin B, Cell Line, Tumor, Toll-Like Receptor 4, Mice

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