Toll-like receptor 3

Evolutionarily, TLRs are ancient, conserved PRRs (Pattern Recognition Receptors).Toll-like receptors primarily serve to recognize so-called "Pathogen Associated Molecular Patterns" ( PAMPs). Meanwhile, in humans, 10 (TLR-1 to 10) and 12 murine (TLR-1 to 9 + 11 and 13). 6 of the human TLRs bind PAMPs extracellularly (TLR-1, 2, 4, 5, 6, 10) while 4 are localized only intracellularly (TLR-3, 7, 8 and 9).

TLRs are expressed by immune cells of the innate immune system and also by cells of the adaptive immune system (B and T cells), as well as by numerous non-immune cells. This wide distribution makes TLRs an excellent tool for the innate and acquired immune system. TLRs thus provide cross-talk for pathogen recognition and activation of "antigen-specific acquired immunity." The activity of TLRs enables innate defense mechanisms (see Immunity, Innate) to distinguish between "self" and "foreign." In pathogen recognition, the various TLRs require different adaptor molecules to activate intracellular signaling cascades, such as: MyD88, TICAM-1 (TRIF), TIRAP/MAL, TRAM, and SARM.

TLR3 activity (see TLR3 gene) leads via phosphorylation ofinterferon regulatory factor 3 (IRF3) and IRF7 to the induction of interferon, namely IFN beta; IFN alpha is not produced. A further signaling cascade activatesnuclear factor kappa B(NFkappaB). This leads to the secretion of inflammatory cytokines. Furthermore, a "mitogen activated protein kinase"-dependent(MAPK) transduction pathway exists.

After TLR3 has recognized its ligand, the transcription of different cytokines is induced following activation of an intracellular signaling cascade. The second signaling pathway activated by TLR3 and TLR4 also leads to the induction of type I interferons via the adapter molecule TRIF and ultimately to cell death via apoptosis or necrosis.

The TLR3 receptor expressed by dendritic cells (DCs) recognizes double-stranded RNA (dsRNA), e.g. of viral origin. However, TLR3 does not play a role in all viral infection models.

TLR3 receptors are bound in intracellular compartments such as the endolysosome. LR3 activates signaling molecules via the TRIF signaling pathway and triggers the release of proinflammatory cytokines, such as the antivirally active interferons.

TLRs thus play an essential role in the recognition and in the induction of an efficient immune response (activates NF-κB via TRIF signaling pathway) in viral infections. For example, impaired TLR3 expression can lead to prolonged hepatitis B.

Under certain circumstances, binding to the ligand (e.g. viral double-stranded RNA) leads to a pathological, perpetuating (autoimmunological) inflammatory response. This pathological mechanism mainly affects intracellular TLRs, such as TLR3, TLR7/8, and TLR9. Such processes are discussed for the induction of type 1 diabetes. Furthermore, for rheumatoid arthritis, systemic lupus erythematosus, systemic scleroderma Sjögren's syndrome, psoriasis vulgaris, and multiple sclerosis (Liu Y et al. 2014) .

Toll-like receptor 3 also recognizes damaged endogenous RNA released from UV-damaged keratinocytes after UV irradiation of the skin, for example. The TLR3 activation induced by this induces local inflammation via the TLR3 signaling pathway (Borkowski AW et al. 2014).

TLR2, TLR3, TLR4, and TLR5 are significantly expressed in normal and neoplastic ovarian epithelium. Apparently, overexpression of TLR3 receptor seems to lead to tumor enhancement (Husseinzadeh N et al 2014).

Several polymorphisms of the TLR3 gene are significantly associated with a higher risk of carcinoma .

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