CDB15:0001330 S100A9 — 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 S100a9 — 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.

S100A9 induces differentiation of acute myeloid leukemia cells through TLR4.

Blood, 2017; PubMed, Homo sapiens S100A9 — Homo sapiens TLR4

ABSTRACT: S100A8 and S100A9 are calcium-binding proteins predominantly expressed by neutrophils and monocytes and play key roles in both normal and pathological inflammation. Recently, both proteins were found to promote tumor progression through the establishment of premetastatic niches and inhibit antitumor immune responses. Although S100A8 and S100A9 have been studied in solid cancers, their functions in hematological malignancies remain poorly understood. However, S100A8 and S100A9 are highly expressed in acute myeloid leukemia (AML), and S100A8 expression has been linked to poor prognosis in AML. We identified a small subpopulation of cells expressing S100A8 and S100A9 in AML mouse models and primary human AML samples. In vitro and in vivo analyses revealed that S100A9 induces AML cell differentiation, whereas S100A8 prevents differentiation induced by S100A9 activity and maintains AML immature phenotype. Treatment with recombinant S100A9 proteins increased AML cell maturation, induced growth arrest, and prolonged survival in an AML mouse model. Interestingly, anti-S100A8 antibody treatment had effects similar to those of S100A9 therapy in vivo, suggesting that high ratios of S100A9 over S100A8 are required to induce differentiation. Our in vitro studies on the mechanisms/pathways involved in leukemic cell differentiation revealed that binding of S100A9 to Toll-like receptor 4 (TLR4) promotes activation of p38 mitogen-activated protein kinase, extracellular signal-regulated kinases 1 and 2, and Jun N-terminal kinase signaling pathways, leading to myelomonocytic and monocytic AML cell differentiation. These findings indicate that S100A8 and S100A9 are regulators of myeloid differentiation in leukemia and have therapeutic potential in myelomonocytic and monocytic AMLs.

Basic Information on S100A9

Ligand Name: S100 calcium binding protein A9

Other Symbols: CAGB, CFAG, P14, MIF, NIF, LIAG, MRP14, MAC387, 60B8AG, CGLB, MRP-14, S100-A9

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

HGNC Gene Symbol Report: S100A9

GeneCards: S100A9

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

Functional Annotations for S100A9

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 S100A9

S100A9 — AGER ・ S100A9 — ALCAM ・ S100A9 — BSG ・ S100A9 — CD14 ・ S100A9 — CD33 ・ S100A9 — CD36 ・ S100A9 — CD68 ・ S100A9 — CD69 ・ S100A9 — MCAM

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 ・ S100A8 — 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