CDB15:0001329 S100A8 — TLR4

Experimentally validated in Human, Mouse; Orthology-inferred in Human, Rat, Frog, Zebrafish, Chicken, Macaque, Pig, Dog, Cow, Chimp, Horse, Marmoset, Sheep, Mouse

Title

Journal:; Year Published:

Abstract

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

Nature medicine, 2007; PubMed, Mus Musculus S100a8 — Mus Musculus Tlr4

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.

Myeloid-related protein 8 induces self-tolerance and cross-tolerance to bacterial infection via TLR4- and TLR2-mediated signal pathways.

Scientific reports, 2015; PubMed, Homo sapiens S100A8 — Homo sapiens TLR4

ABSTRACT: Myeloid-related protein 8 (Mrp8) is the active component of Mrp8/14 protein complex released by phagocytes at the site of infection and stimulates inflammatory responses. However, it is unclear whether Mrp8 could induce self-tolerance and cross-tolerance to bacterial infection. Here we report that Mrp8 triggered TNF-α and IL-6 release via a Toll-like receptor 4 (TLR4)-dependent manner. Pre-stimulation of murine macrophages and human monocytes with Mrp8 induced self-tolerance to Mrp8 re-stimulation and cross-tolerance to lipopolysaccharide (LPS), bacterial lipoprotein (BLP), gram-negative and gram-positive bacterial challenges, with substantially attenuated TNF-α and IL-6 release. Moreover, Mrp8 tolerisation significantly reduced serum TNF-α and IL-6, increased polymorphonuclear neutrophil (PMN) recruitment and accelerated bacterial clearance, thus protecting mice against LPS-induced lethality and cecal ligation and puncture (CLP)-induced polymicrobial sepsis. In addition to TLR4, TLR2 also contributed to Mrp8-induced inflammatory response and tolerance. Down-regulation of phosphorylated p38 by Mrp8 pre-stimulation was predominantly responsible for the intracellular mechanism of Mrp8-induced tolerance. Thus, our findings of Mrp8-induced self-tolerance and cross-tolerance may provide a potential strategy for attenuating an overwhelming proinflammatory cascade and enhancing antimicrobial responses during microbial sepsis.

Basic Information on S100A8

Ligand Name: S100 calcium binding protein A8

Other Symbols: CAGA, CFAG, P8, MRP8, MRP-8, 60B8AG, CGLA, S100-A8

Ligand Location: secreted based on hpa, perplexity, uniprot, cell membrane based on uniprot

HGNC Gene Symbol Report: S100A8

GeneCards: S100A8

HGNC Gene Group: Epidermal differentiation complex, EF-hand domain containing

Functional Annotations for S100A8

Gene Ontologies: PAN-GO, AmiGO 2

Expression Profile: Human Protein Atlas (RNA and protein), Human Cell Atlas (RNA), GEPIA cancer vs normal (RNA), GeneCards (RNA and protein)

Disease Annotations: MalaCards, OMIM, Open Targets Platform, DISEASES (text mining), AI summary (LLM)

Interactions with other Receptors for S100A8

S100A8 — AGER ・ S100A8 — ALCAM ・ S100A8 — CD36 ・ S100A8 — CD68 ・ S100A8 — CD69 ・ S100A8 — LY96 ・ S100A8 — MCAM ・ S100A8 — NPTN ・ S100A8 — TLR2

Basic Information on TLR4

Receptor Name: toll like receptor 4

Other Symbols: hToll, CD284, TLR-4, ARMD10

Receptor Location: cell membrane based on hpa, perplexity, uniprot

HGNC Gene Symbol Report: TLR4

GeneCards: TLR4

HGNC Gene Group: TIR domain containing, CD molecules

Functional Annotations for TLR4

Gene Ontologies: PAN-GO, AmiGO 2

Expression Profile: Human Protein Atlas (RNA and protein), Human Cell Atlas (RNA), GEPIA cancer vs normal (RNA), GeneCards (RNA and protein)

Disease Annotations: MalaCards, OMIM, Open Targets Platform, DISEASES (text mining), AI summary (LLM)

Interactions with other Ligands for TLR4

BGN — TLR4 ・ DEFB4A — TLR4 ・ HSP90B1 — TLR4 ・ HSPA1A — TLR4 ・ S100A9 — TLR4 ・ SFTPD — TLR4 ・ ZG16B — TLR4 ・ DCN — TLR4 ・ FGA — TLR4 ・ FGB — TLR4 ・ FGG — TLR4 ・ PRG4 — TLR4 ・ AHSG — TLR4 ・ ANXA2 — TLR4 ・ CCN1 — TLR4 ・ CIRBP — TLR4 ・ CXCL10 — TLR4 ・ FCN2 — TLR4 ・ HMGB1 — TLR4 ・ HP — TLR4 ・ HSPA4 — TLR4 ・ LGALS9 — TLR4 ・ MMP9 — TLR4 ・ NAMPT — TLR4 ・ RBP4 — TLR4 ・ RETN — TLR4 ・ S100A1 — TLR4 ・ S100A12 — TLR4 ・ S100A4 — TLR4 ・ SAA1 — TLR4 ・ SFTPA1 — TLR4 ・ TNC — TLR4 ・ WNT5A — TLR4