Toll-like receptor 4

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, which recruits molecules that also contain a TIR domain, but can 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 by immune cells of the innate 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 both the innate and the acquired immune system. TLRs thus provide an overarching tool 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.

After TLR4 has recognized its ligand, the activation of an intracellular signalling cascade induces the transcription of different cytokines. A second signalling pathway activated by TLR3 and TLR4 passes through the adapter molecule TRIF and also leads to the induction of type I interferons.

In endothelial cells, bacterial lipopolysaccharides (LPS) induce a signalling cascade with a consecutive inflammatory response by activating the Toll-like receptor 4 (TLR4). Angiopoietin-1 can inhibit this TLR4-induced inflammation.

In experimental approaches L. acidophilus treatment leads to a reduced expression of TRL4 and NF-κB in peripheral blood mononuclear cells. This requires an inhibition of TNF-α, IFN-γ, interleukin-6, interleukin-8 and interleukin-1B1 and an induction of interleukin-4 and interleukin-10.

A dysfunction of the Toll-like receptor 4 (TLR4) is closely associated with the progression of various carcinomas. For example, TLR4 may enhance angiogenesis in pancreatic cancer by activating the PI3K/AKT signaling pathway.

After cerebral ischemia or traumatic brain damage, an increase in cytoplasmic TLR4 is observed in the hippocampus in animal experiments.

In ischemia-reperfusion experiments, TLR4-induced inflammation occurs after a cerebral infarction after detection of the released pathogens by TLR4. Brain damage and neurological deficits could be largely compensated by glycyrrhizin, an anti-inflammatory phytotherapeutic agent. An analogous effect was also demonstrated in mutant TLR4-deficient animals.

Animal experiments have shown that green tea polyphenols modulate functional lymphocyte parameters. A reduction of pro-inflammatory cytokines such as interleukin-2, interleukin-6, interleukin-1β, TNF-α was detectable. Furthermore, a reduced expression of TRL4 was observed.

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2. Fang J et al (2010) The role of TLR2, TRL3, TRL4, and TRL9 signaling in the pathogenesis of autoimmune disease in a retinal autoimmunity model. Invest Ophthalmol Vis Sci 51:30923099.
3. Kim EC et al,(2015) TMEM126A, a CD137 ligand binding
4. protein, couples with the TLR4 signal transduction pathway in macrophages. Mol immunol 64:244-251.
5. Lee SI et al.(2016) Lactobacillus acidophilus modulates
6. inflammatory activity by regulating the TLR4 and NF-κB expression in porcine peripheral blood mononuclear cells after lipopolysaccharide challenge. Br J Nutr 2115:567-575.
7. Molina N et al(2015)Green tea polyphenols change the profile of inflammatory cytokine release from lymphocytes of obese and lean rats and protect against oxidative damage. Int Immunopharmacol 28:985-996.
8. Sun Y et al(2016) Toll-like receptor 4 promotes angiogenesis in pancreatic cancer via PI3K/AKT signaling. Exp Cell Res 347:274-282.