Toll-like receptor 7

In evolutionary terms, TLRs are old, conserved PRRs (Pattern Recognition Receptors).Toll-like receptors are primarily used to recognize 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. This is followed by a transmembrane domain. Signal transduction takes place via the cytoplasmic "Toll-interleukin-1 receptor homology" domain, TIR for short. This recruits molecules that also contain a TIR domain, but can differ from TLR to TLR.

Toll-like receptor 7 belongs to the family of Toll-like receptors (TLR7), which play a fundamental role in the recognition of pathogens and the activation of innate immunity. Toll-like receptor 7 is encoded by the TLR7 gene, which is located on chromosome Xp22.2.

TLRs are highly conserved from Drosophila to humans and show structural and functional similarities. The human TLR family comprises 11 members (TLT1-TLR11). Toll-like receptors (TLRs) are single transmembrane cell surface receptors that play a key role in the innate immune system. TLRs generally exist as homodimers and are found on immune cells, macrophages, B lymphocytes and mast cells. TLRs recognize pathogen-associated molecular patterns (PAMPs) expressed on infectious agents and mediate the production of cytokines necessary for the development of effective immunity. The different TLRs also have different expression patterns for the recognition of structural components in foreign microorganisms; for example, TLR3, -7 and -8 are essential for the recognition of single-stranded RNA viruses. TLR7 recognizes single-stranded RNA oligonucleotides containing guanosine- and uridine-rich sequences of RNA viruses, whereby this recognition takes place in the endosomes of plasmacytoid dendritic cells and B cells.

The activity of TLRs enables the innate defense mechanisms (see below Immunity, innate) to differentiate between "self" and "foreign". When recognizing pathogens, the various TLRs require different adaptor molecules to activate 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). Apparently, this recognition is motif dependent and less dependent on the content of guanosine (G) and uridine (U) of the ssRNA.

Extracellular ssRNA can only occur when endogenous or foreign cells have died. In any case, this condition is evaluated by the immune system as a danger signal. An inflammatory reaction is triggered via TLR7/TLR8.

Toll-like receptors play a role in the development of cancer. There is a whole range of TLR agonists. Only the topically available TLR7-agonists have proven to be useful therapeutics in tumor therapy (Wang C et al. 2015). The main target cell of TLR7 agonists are IFN-α -producing plasmacytoid dendritic cells. They are the starting point of an adaptive immune response. Besides NK cells, antigen-specific T cells are the effectors of the TLR7 agonist reaction.

Imiquimod and loxoribin are such agonists of the Toll-like receptor 7 (TLR7). Imiquimod, as a meanwhile approved preparation, has proven to be an efficient topical agent for the treatment of superficial basal cell carcinoma. A functional X-linked TLR7 rs179008/Gln11Leu polymorphism of the TLR7 receptor leads to a reduction of the clinical efficacy of Imiquimod.

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

1. Kobold S et al (2014) Modes of action of TLR7 agonists in cancer therapy. Immunotherapy 6:1085-1095
   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.
2. Piaserico S et al (2015) TLR7 Gln11Leu single nucleotide polymorphism and response to treatment with imiquimod in patients with basal cell carcinoma: a pilot study. Pharmacogenomics 16:1913-1937.
3. Zhang L et al (2015) The TLR7 agonist Imiquimod promote the immunogenicity of mesenchymal stem cells. Biol Res 48:6.
4. 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.