Toll-like receptor 8

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 T cells) as well as in various epithelial cells (e.g. intestinal epithelia). This wide distribution makes TLRs an excellent tool for both the innate and the 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 natural ligand for the dimeric receptor TLR7/TLR8 is single-stranded RNA (ssRNA), as found in viruses, but also in human cells or in the form of so-called synthetic oligoribonucleotides (ORN). Obviously, this recognition is motif dependent (Hornung V et al. 2008). While long ssRNA is easily recognised by TLR7 and TLR8, recognition seems to work reliably with short RNA oligonucleotides only if certain sequence motifs for TLR7 and TLR8, so-called "is RNA = immunostimulatory RNA" are present.

Extracellular ssRNA is only present if endogenous or foreign cells have died. In any case, this condition is evaluated by the immune system as a danger signal. Extracellular ssRNA is recognized via TLR7/TLR8 and an inflammatory reaction is triggered.

Keratinocytes express several TLRs. This fact has led to an understanding of the pathogenesis of psoriasis. For example, TLR9-activated keratinocytes secrete type 1 interferons. Antagonists of TLR7 and TLR8 as well as anti-IL-12/IL-23 antibodies show good clinical therapy results in this disease (Rahmani F et al. 2016).

Several TLR agonists are in clinical or preclinical testing for the indications bronchial asthma or allergic rhinosinusitis (CRX-675:TLR4 agonist; AZD8848: TLR7 agonist; VTX-1463:TLR8 agonist, 1018 ISS and QbG10:TLR9 agonists - Horak F 2011; Aryan Z et al.2015)

The rationale for this therapeutic approach A is the finding that TLR-agonists reduce the allergen-triggered Th2 immune response and thus the overreactivity of the respiratory mucosa.

Polymorphisms of TLR7 and TLR9 are associated with the development of systemic lupus erythematosus in Asian populations.

1. Aryan Z et al(2015) Toll-like receptors as targets for allergen immunotherapy. Curr Opin Allergy Clin Immunol 15:568-574.
2. Horak F (2011) VTX-1463, a novel TLR8 agonist for the treatment of allergic rhinitis. Expert Opinion Investig Drugs. 20:981-986.
3. Hornung V et al (2008) RNA recognition via TLR7 and TLR8. Handb Exp Pharmacol 183:71-86.
4. Lee YH et al (2012) Associations between TLR polymorphisms and systemic lupus erythematosus: a systematic review and meta-analysis. Clin Exp Rheumatol 30:262-265. https://www.ncbi.nlm.nih.gov/pubmed/22325161
5. Rahmani F et al(2016) Therapeutic targeting of Toll-like receptors: a review of Toll-like receptors and their signaling pathways in psoriasis. Expert Rev Clin Immunol 12:1289-1298. https://www.ncbi.nlm.nih.gov/pubmed/27359083
6. Wang C et al (2015) The TLR7 agonist induces tumor regression both by promoting CD4⁺T cells proliferation and by reversing T regulatory cell-mediated suppression via dendritic cells. Oncotarget 6:1779-1789.