TLR3 is a member of the toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved fromDrosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production ofcytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed inplacenta andpancreas, and is restricted to thedendritic subpopulation of theleukocytes. It recognizesdsRNA associated with viral infection, and induces the activation ofIRF3 andNF-κB.[6] Unlike other TLRs, TLR3 uses TRIF as the sole adaptor.[6] IRF3 ultimately induces the production of type Iinterferons. It may thus play a role in host defense against viruses.[7]
TLR3 recognizes double-strandedRNA, a form of genetic information carried by someviruses such asreoviruses. Additionally, an ephemeral form of double-stranded RNA exists as a replicative intermediate during virus replication.[8] Upon recognition, TLR3 induces the activation of IRF3 to increase production oftype I interferons which signal other cells to increase their antiviral defenses.Double-stranded RNA is also recognised by the cytoplasmic receptorsRIG-I andMDA-5.[9]
TLR3 displays a protective role in mouse models ofatherosclerosis,[10] and activation of TLR3 signaling is associated with ischemic preconditioning-induced protection against brain ischemia and attenuation of reactive astrogliosis.[11][12] Furthermore, TLR3 activation has been shown to promote hair follicle regeneration in skin wound healing.[13] In addition, TLR3 activators show effects on human vascular cells.[10]
The structure of TLR3 was reported in June 2005 by researchers atThe Scripps Research Institute.[14] TLR3 forms a large horseshoe shape that contacts with a neighboring horseshoe, forming a "dimer" of two horseshoes. Much of the TLR3 protein surface is covered withsugar molecules, making it aglycoprotein, but on one face (including the proposed interface between the two horseshoes), there is a large sugar-free surface. This surface also contains two distinct patches rich in positively chargedamino acids, which may be a binding site for negatively charged double-stranded RNA.
