TLR4
GeneName
TLR4
Summary
TLR4, also known as Toll-like receptor 4, is a 96kDa transmembrane protein primarily expressed on the surface of immune cells such as macrophages and dendritic cells. It plays a crucial role in the innate immune response by recognising lipopolysaccharides (LPS) from Gram-negative bacteria, which triggers a cascade of signalling events that lead to the activation of immune responses. TLR4 is localised to various cellular compartments, including the plasma membrane and early endosomes, and is involved in processes such as phagocytosis, macrophage activation, and the regulation of inflammatory responses. Additionally, TLR4 has been implicated in the cellular response to amyloid-beta, linking it to neuroinflammatory processes.
Importance
TLR4 is relevant to: - The innate immune response, particularly in the detection and response to bacterial infections, influencing the development of sepsis and other inflammatory diseases. - Autoimmune diseases and neurodegenerative disorders, such as Alzheimer’s disease, due to its role in mediating inflammation and amyloid-beta responses. - Cancer immunotherapy, as TLR4 activation can enhance anti-tumour immunity through the promotion of dendritic cell maturation and T cell activation. - Research into therapeutic targets for inflammatory conditions, given its central role in mediating responses to various stimuli, including lipopolysaccharides and cytokines.
Top Products
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Abcam Product Citation Summary
The data indicates a significant focus on TLR4 in various biological contexts, particularly in studies related to inflammation, immune response, and tissue injury across multiple species, predominantly Mus musculus and human samples. The applications of the antibodies include Western blotting and immunohistochemistry, highlighting their utility in examining TLR4's role in different pathological conditions.
Abcam Product Citation Table
Domain
The TIR domain mediates interaction with NOX4.
Function
Transmembrane receptor that functions as a pattern recognition receptor recognizing pathogen- and damage-associated molecular patterns (PAMPs and DAMPs) to induce innate immune responses via downstream signaling pathways (PubMed:10835634, PubMed:15809303, PubMed:16622205, PubMed:17292937, PubMed:17478729, PubMed:20037584, PubMed:20711192, PubMed:23880187, PubMed:27022195, PubMed:29038465). At the plasma membrane, cooperates with LY96 to mediate the innate immune response to bacterial lipopolysaccharide (LPS) (PubMed:27022195). Also involved in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+) (PubMed:20711192). Mechanistically, acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response (PubMed:10835634, PubMed:21393102, PubMed:27022195, PubMed:36945827, PubMed:9237759). Alternatively, CD14-mediated TLR4 internalization via endocytosis is associated with the initiation of a MYD88-independent signaling via the TICAM1-TBK1-IRF3 axis leading to type I interferon production (PubMed:14517278). In addition to the secretion of proinflammatory cytokines, initiates the activation of NLRP3 inflammasome and formation of a positive feedback loop between autophagy and NF-kappa-B signaling cascade (PubMed:32894580). In complex with TLR6, promotes inflammation in monocytes/macrophages by associating with TLR6 and the receptor CD86 (PubMed:23880187). Upon ligand binding, such as oxLDL or amyloid-beta 42, the TLR4:TLR6 complex is internalized and triggers inflammatory response, leading to NF-kappa-B-dependent production of CXCL1, CXCL2 and CCL9 cytokines, via MYD88 signaling pathway, and CCL5 cytokine, via TICAM1 signaling pathway (PubMed:23880187). In myeloid dendritic cells, vesicular stomatitis virus glycoprotein G but not LPS promotes the activation of IRF7, leading to type I IFN production in a CD14-dependent manner (PubMed:15265881, PubMed:23880187). Required for the migration-promoting effects of ZG16B/PAUF on pancreatic cancer cells.
Post-translational modifications
N-glycosylated. Glycosylation of Asn-526 and Asn-575 seems to be necessary for the expression of TLR4 on the cell surface and the LPS-response. Likewise, mutants lacking two or more of the other N-glycosylation sites were deficient in interaction with LPS.
Phosphorylated on tyrosine residues by LYN after binding lipopolysaccharide.
Sequence Similarities
Belongs to the Toll-like receptor family.
Tissue Specificity
Highly expressed in placenta, spleen and peripheral blood leukocytes (PubMed:9237759, PubMed:9435236). Detected in monocytes, macrophages, dendritic cells and several types of T-cells (PubMed:27022195, PubMed:9237759). Expressed in pancreatic cancer cells but not in normal pancreatic cells (at protein level) (PubMed:36232715).
Cellular localization
- Cell membrane
- Single-pass type I membrane protein
- Early endosome
- Cell projection
- Ruffle
- Upon complex formation with CD36 and TLR6, internalized through dynamin-dependent endocytosis (PubMed:20037584). Colocalizes with RFTN1 at cell membrane and then together with RFTN1 moves to endosomes, upon lipopolysaccharide stimulation. Co-localizes with ZG16B/PAUF at the cell membrane of pancreatic cancer cells (PubMed:36232715).
Alternative names
CD284, Toll-like receptor 4, hToll, TLR4
Database links
swissprot:O00206 omim:603030 entrezGene:7099
Other research areas
- Immuno-oncology
- Neuroscience
- Oncology