Toll-like receptor 6

In evolutionary terms, TLRs are old, conserved PRRs (Pattern Recognition Receptors); Toll-like receptors are primarily used for the recognition of so-called "Pathogen Associated Molecular Patterns" (PAMPs). TLRs are transmembrane glycoproteins. Their extracellular, N-terminal domain consists of an LRR that specifically binds different ligands. A transmembrane domain follows. The signal transduction takes place through the cytoplasmic "Toll-interleukin-1 receptor homology" domain, TIR for short. This recruits molecules that also contain a TIR domain, but which may differ from TLR to TLR.

In humans, there are now 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 only localized intracellularly (TLR-3, 7, 8 and 9).

TLRs are expressed in immune cells of the innate and also of cells of the adaptive immune system (B- and CD286+ T-cells) as well as in various epithelial cells (e.g. intestinal epithelia, McDermott AJ et al. 2014; Husseinzadeh N et al. 2014). This wide distribution makes TLRs an excellent tool for the innate and acquired immune system. TLRs are thus responsible for the recognition of pathogens and the activation of antigen-specific acquired immunity. Through the activity of TLRs, the innate defence mechanisms (see below immunity, innate) can distinguish between "self" and "foreign". For the detection of pathogens, the TLRs need different adaptor molecules for the activation of intracellular signalling cascades such as: MyD88, TICAM-1 (TRIF), TIRAP/MAL, TRAM, and SARM.

The TLR6 receptor interacts functionally with the Toll-like receptor 2 and induces cellular responses to bacterial lipoproteins.

TLR6/TLR2 is expressed on the cell surface and recognizes FDi-acetylated lipoproteins of bacteria. Including the adaptor molecules MyD88 and TRIF, which are important regulators for the activation of the receptor in the small intestine (Brandão I et al. 2015), a signalling cascade is triggered in TLR6 cells. This leads to phosphorylation and thus to the activation of intracellular kinases. Their task is the phosphorylation of intracellular inhibitors of transcription factors. This causes the inhibitors to lose their inhibitory effect. Transcription factors are released and translocated into the cell nucleus. There they regulate the expression of various genes that organise the defence against infection.

A connection between the intestinal microbiome and the development of "non-alcoholic fatty liver" is undisputed. The toll-like receptors TLR2/6, TLR4, TLR5 and TLR9 play a pathogenetic role. A change in the intestinal microbiome alters the nutritive absorption and storage. Microbiotics are inducers of ligands of the toll-like receptors, which in turn induce proinflammatory cytokines in liver cells (Miura K et al. 2014)

TLR6 and the TLR1/TLR2 dimers play a modulating role in the pathogenesis of acne vulgaris.

TLR2/TLR6, TLR3, TLR4 and TLR5 are significantly expressed in normal and neoplastic ovarian epithelia (Husseinzadeh N et al. 2014).

Polymorphisms in the genes encoding TLR1, TLR2, TLR4, TLR6 lead to a number of diseases.

The "6 V327M polymorphism" of the Toll-like receptor gene is associated with an increased risk of developing Klebsiella pneumoniae infection.

The "Ser249Pro" polymorphism in the extracellular domain of the toll-like receptor gene is associated with an increased risk of bronchial asthma in certain human populations.

1. Kim J (2005) Review of the innate immune response in acne vulgaris: activation of Toll-like receptor 2 in acne triggers inflammatory cytokine responses. Dermatology 211:193-198.
2. Noreen M et al (2015) Association of TLR1, TLR2, TLR4, TLR6, and TIRAP polymorphisms with disease susceptibility. Immunol Res 62: 234-252.
3. Schurz H et al (2015) TLR1, 2, 4, 6 and 9 Variants Associated with Tuberculosis Susceptibility: A Systematic Review and Meta-Analysis. PLoS One 10:e0139711.
4. Yang H et al (2014) Toll-like receptor 6 V327M polymorphism is associated with an increased risk of Klebsiella pneumoniae infection. J Pediatric Infect Dis 33:e310-315.
5. Zhang Y et al (2013) Toll-like receptor -1, -2, and -6 polymorphisms and pulmonary tuberculosis susceptibility: a systematic review and meta-analysis. PLoS One 8:e63357.