Toll-like receptor 5

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, 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.

TLR5 is expressed on the cell surface and recognizes flagellin (Miao EA et al. 2007), which is found in Gram-positive and Gram-negative flagellated bacteria (including Borrelia). Involving the adaptor molecules MyD88 and TICAM1, which are important regulators for the activation of the receptor in the small intestine (Brandão I et al. 2015), a signaling cascade is triggered in the TLR5 cells. This leads to phosphorylation and thus to the activation of intracellular kinases. Their task is to phosphorylate intracellular inhibitors of transcription factors. As a result, the inhibitors lose their inhibitory effect. Transcription factors are released and translocated into the cell nucleus. There they regulate the expression of various genes that organize the defence against infection.

In contrast to other TLRs, TLR5 is not expressed by conventional dendritic cells or macrophages, but is expressed in non-professional immune cells such as intestinal CD11⁽⁺⁾ lamina propria cells (LPCs), which do not express TLR4. LPCs detect pathogenic bacteria, secrete proinflammatory cytokines and induce the differentiation of naïve B cells into IgA(+) plasma cells. They also trigger the differentiation of antigen-specific Th17 and Th1 lymphocytes (Uematsu S 2009).

The toll-like receptors TLR2, TLR4, and TLR5 play an important and initiating role in integrin-dependent neutrophil adhesion (Subramanian P et al. 2016). Neutrophil granulocytes, which play an essential role in acute infections and inflammations, formulate together with other cells a first line of defense against invading pathogens. Their tissue invasion requires adhesion and transmigration through blood vessels, which are adjusted by adhesion molecules such as beta2- and beta1-integrins, chemokines and other cytokines.

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

TLR2, TLR3, TLR4 and TLR5 are markedly expressed in normal and neoplastic ovarian epithelia. Overexpression of the TLR3 receptor appears to lead to tumor enhancement (Husseinzadeh N et al. 2014).

1. Brandão I et al. (2015) TLR5 expression in the small intestine depends on the adaptors MyD88 and TRIF, but is independent of the enteric microbiota. Gut Microbes 6:202-206.
2. Husseinzadeh N et al. (2014) Role of toll-like receptors in cervical, endometrial and ovarian cancers: a review. Gynecol Oncol 135:359-363.
3. McDermott AJ et al.(2014) The microbiome and regulation of mucosal immunity. Immunology 142:24-31.
4. Miao EA et al.(2007) TLR5 and Ipaf: dual sensors of bacterial flagellin in the innate immune system. Semin Immunopathol 29:275-288.
5. Miura K et al.(2014) Role of gut microbiota and Toll-like receptors in nonalcoholic fatty liver disease. World J Gastroenterol 20:7381-7391.
6. Subramanian P et al. (2016) Regulation of tissue infiltration by neutrophils: role of integrin α3β1 and other factors. Curr Opin Hematol 23:36-43.
7. Uematsu S (2009).TLR5+ DC-mediated immune response to bacterial infection in the intestine. Tanpakushitsu Kakusan Koso 54 (8 Suppl):1020-1026. review.