TLR4
Description
The TLR4 (toll like receptor 4) is a protein-coding gene located on chromosome 9.
Toll-like receptor 4 (TLR4), also designated as CD284, is a key activator of the innate immune response and plays a central role in the fight against bacterial infections. TLR4 is a transmembrane protein of approximately 95 kDa that is encoded by the TLR4 gene. TLR4 belongs to the toll-like receptor family, which represents the pattern recognition receptors (PRR). PRRs are named for their ability to recognize evolutionarily conserved components of microorganisms (bacteria, viruses, fungi, and parasites), called pathogen-associated molecular patterns (PAMPs). The recognition of a PAMP by a PRR triggers rapid activation of the innate immunity essential to fight infectious diseases. TLR4 is expressed in immune cells mainly of myeloid origin, including monocytes, macrophages, and dendritic cells (DC). It is also expressed at a lower level on some non-immune cells, including epithelium, endothelium, placental cells, and beta cells in Langerhans islets. Most myeloid cells express also high amounts of plasma membrane-anchored CD14, which facilitates the activation of TLR4 by LPS and controls the subsequent internalization of the LPS-activated TLR4 important for receptor signaling and degradation. The main ligands for TLR4 are lipopolysaccharides (LPS), the major components of the outer membrane of Gram-negative bacteria and some Gram-positive bacteria. TLR4 can also be activated by endogenous compounds called damage-associated molecular patterns (DAMPs), including high mobility group box protein 1 (HMGB1), S100 proteins, or histones. These compounds are released during tissue injury and by dying or necrotic cells.
TLR4 is a transmembrane receptor that acts as a pattern recognition receptor (PRR) to recognize both pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). This recognition triggers innate immune responses by activating downstream signaling pathways, ultimately leading to the production of pro-inflammatory cytokines. TLR4 cooperates with LY96 at the plasma membrane to mediate the innate immune response to bacterial lipopolysaccharide (LPS). It also participates in LPS-independent inflammatory responses triggered by free fatty acids, such as palmitate, and Ni(2+). Mechanistically, TLR4 acts via the MYD88, TIRAP, and TRAF6 signaling pathway, resulting in NF-kappa-B activation, cytokine secretion, and inflammation. Alternatively, CD14-mediated TLR4 internalization via endocytosis can initiate a MYD88-independent signaling cascade through the TICAM1-TBK1-IRF3 axis, leading to type I interferon production. Besides cytokine secretion, TLR4 activates the NLRP3 inflammasome and establishes a positive feedback loop between autophagy and the NF-kappa-B signaling cascade. In complex with TLR6, TLR4 promotes inflammation in monocytes/macrophages by associating with TLR6 and the receptor CD86. Upon binding to ligands like oxLDL or amyloid-beta 42, the TLR4:TLR6 complex is internalized and triggers inflammatory responses, resulting in the NF-kappa-B-dependent production of CXCL1, CXCL2, and CCL9 cytokines via the MYD88 pathway, as well as CCL5 cytokine via the TICAM1 pathway. In myeloid dendritic cells, vesicular stomatitis virus glycoprotein G, but not LPS, activates IRF7, leading to type I IFN production in a CD14-dependent manner. TLR4 is crucial for the migration-promoting effects of ZG16B/PAUF on pancreatic cancer cells.
TLR4 is also known as ARMD10, CD284, TLR-4, TOLL.
