Toll-like receptor 3

Function

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 from Drosophila 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 of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This receptor is most abundantly expressed in placenta and pancreas, and is restricted to the dendritic subpopulation of the leukocytes. It recognizes dsRNA associated with viral infection, and induces the activation of IRF3 and NF-κB. Unlike other TLRs, TLR3 uses TRIF as the sole adaptor. IRF3 ultimately induces the production of type I interferons. It may thus play a role in host defense against viruses.

TLR3 recognizes double-stranded RNA, a form of genetic information carried by some viruses such as reoviruses. Additionally, an ephemeral form of double-stranded RNA exists as a replicative intermediate during virus replication. Upon recognition, TLR3 induces the activation of IRF3 to increase production of type I interferons which signal other cells to increase their antiviral defenses. Double-stranded RNA is also recognised by the cytoplasmic receptors RIG-I and MDA-5.

TLR3 displays a protective role in mouse models of atherosclerosis, and activation of TLR3 signaling is associated with ischemic preconditioning-induced protection against brain ischemia and attenuation of reactive astrogliosis. Furthermore, TLR3 activation has been shown to promote hair follicle regeneration in skin wound healing. In addition, TLR3 activators show effects on human vascular cells.

Structure

The structure of TLR3 was reported in June 2005 by researchers at The Scripps Research Institute. 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 with sugar molecules, making it a glycoprotein, 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 charged amino acids, which may be a binding site for negatively charged double-stranded RNA.

Despite being a glycoprotein, TLR3 crystallises readily – a prerequisite for structural analysis by x-ray crystallography.

Ligands

; Antagonists

• CU-CPT4a

References

References

1. (January 1998). "A family of human receptors structurally related to Drosophila Toll". Proceedings of the National Academy of Sciences of the United States of America.
2. (November 2007). "Signaling to NF-kappaB by Toll-like receptors". Trends in Molecular Medicine.
3. "Entrez Gene: toll-like receptor 3".
4. (2012). "Medical Microbiology". Churchill Livingstone.
5. (October 2001). "Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3". Nature.
6. (February 2011). "Unexpected protective role for Toll-like receptor 3 in the arterial wall". Proceedings of the National Academy of Sciences of the United States of America.
7. (2014). "Astrocytic Toll-like receptor 3 is associated with ischemic preconditioning-induced protection against brain ischemia in rodents". PLOS ONE.
8. (November 2015). "TLR3 ligand Poly IC Attenuates Reactive Astrogliosis and Improves Recovery of Rats after Focal Cerebral Ischemia". CNS Neuroscience & Therapeutics.
9. (August 2015). "dsRNA Released by Tissue Damage Activates TLR3 to Drive Skin Regeneration". Cell Stem Cell.
10. (July 2005). "Crystal structure of human toll-like receptor 3 (TLR3) ectodomain". Science.