Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

TLR8

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101876

Synonyms

Historical Background

Although sharing a similar structure, genomic localization, and involvement in RNA sensing, TLR7 and TLR8 are found in distinct immune cells (Hornung et al. 2002). This selective expression correlates with distinct biological functionality and production of type I IFNs (Gorden et al. 2005; Cervantes et al. 2011).

The initial observations that TLR8-deficient mice did not show any defect in nucleic acid detection, due to a lack of response to imidazoquinolines and RNA (Heil et al. 2004; Jurk et al. 2002), lead to a relative lack of interest in this particular endosomal TLR. Very recently it has been reported that overexpression of mTLR8 is required for the activation of transcription factor NF-κB and the production of TNF-α (Li et al. 2016). These results demonstrate that mTLR8 is indeed functional and does play a role in the activation of innate immune responses.

Structural Features of the TLR8 Ligand Recognition Domain

TLR8 gene is located on chromosome X from mice to humans. TLR8 recognizes uridine- and guanosine-rich single-stranded RNA (ssRNA) from viruses and bacteria and can also be activated by some guanine nucleotide analogs and a large number of synthetic chemical agonists such as imidazoquinolines (Chai et al. 2016). TLR8 belongs to type I transmembrane receptors and is composed of three domains, the extracellular domain (ECD), a transmembrane domain, and a cytoplasmic Toll/IL-1 receptor (TIR) domain, which is required for the transduction of downstream signaling (Tanji et al. 2013). The ECD is responsible for ligand recognition and is consisted of 20–26 leucine-rich repeats (LRRs), each folded in a β-sheet with a hydrophobic leucine-rich sequence motif and a 3–4 turned α-helix connected by loops. When the consensus LRRs are assembled to an ECD, the domain frame shows a horseshoe-shaped structure and has differently ordered architectures on both sides; their inner surface is more closely fitted by well-sorted parallel β-sheets, whereas the outer surface has irregularly organized α-helixes and loops that allow a curved releasing configuration. TLR8 has a characteristic insertion loop (Z-loop) of almost 40 amino acids. TLR8 is considered to be dimeric in the absence of ligands, and it is transported into an activated dimer upon ligand binding which allows for dimerization of the intracellular TIR domains and subsequent signaling (Song and Lee 2012). The crystal structures of TLR8-ECD dimer show “M”-shaped dimeric forms that are well suited for ligand binding (Tanji et al. 2013). The human TLR8-ECD monomers appear far away from the dimerization partners at the C-terminus regions by ∼53 Å, but upon small ligand binding, they were brought into closer proximity (30–34 Å) to the signaling complex structure (within the ligand-induced dimerization structures represented in Fig. 1). In addition, the ligand-induced activated forms of TLR8-ECDs are well aligned in comparison to that of the unliganded dimer. Interestingly, these ligands that are kept in the TLR8-ECD binding pockets are identically duplicated. In the known TLR8-ECD dimers in which each ECD binds an agonistic ligand, two ligand-binding sites are located on both lateral interfaces of an “M”-shaped ECD dimer immediately adjacent to the acidic ambiences. The Z-loop protrudes from the lateral surface and is faced with the unit of ligand-binding cavity. A recent study revealed that the uncleaved Z-loop located on the ascending lateral face prevents the approach of the dimerization partner owing to steric hindrances and cannot form the preformed and subsequently activated dimer (Tanji et al. 2016). The cleaved Z-loop interacts with LRRs to stabilize the TLR8 structure and contributes to ligand recognition by making contact with the inner face of the LRR structure.
TLR8, Fig. 1

TLR8 dimer structures of the liganded ORN06 and CL097 complexes. The Z-loop is shown in pink stick

Binding the Agonist Ligands with TLR8 Homodimer

On the interactions of cocrystalized structures with small agonists such as thiazoloquinolone (CL075 and CL097) in the dimerization interface of human TLR8 receptor, the three-membered rings are in the same position, and the imidazole group is in a similar position to the thiazole or the oxazole functional groups in which the core scaffolds overlay very closely on the imidazoquinoline substructure of R848, except the nucleotide mimetic ligand of ORN06S (PDB ID code 4R09) (Tanji et al. 2015). The binding pockets are composed of Asp543, Asp545, Gly572, Val573, and Thr574 of TLR8 monomer and Phe346, Tyr348, Ile349, Gly351, Ser352, Tyr353, Gly376, Val378, and Phe405 of its dimerization partner with its small agonist ligands (CL075, CL097, and R848). The key interactions occur between TLR8 and its ligands:
  1. i.

    π-π stacking interactions between the aromatic rings of the ligands and Phe405 of TLR8.

     
  2. ii.

    Two H-bonds are also formed between N atoms of the quinolone and of the imidazole groups of the ligands to the side chain of Thr574 of TLR8 and between the amine group of the ligands and Asp543 of TLR8.

     
  3. iii.

    There the 2-propyl (CL075) and the 2-ethoxymethyl (R848 and CL097) substituent in the hydrophobic cavity is formed by Phe346, Tyr348, Gly376, Val378, Ile403, Phe405, Gly572, and Val573 of TLR8-ECD dimer.

     

The ORN06S oligonucleotide has a completely different binding pattern and binding geometry corresponding to the interaction counterpart residues against the former ligands, in the key π-π stacking interactions of His373, His469, Lys314, or Arg375 and H-bond of Asp343, Arg375, Glu340, Tyr291, and Asn400 in the TLR8 binding sites. ORN06 and quinolone derivatives (CL075, CL097, and R848) differ in molecular sizes and in electrostatic properties between them (Fig. 1).

The liganded TLR8-ECD dimer leads to the rearrangement of dimerization of both TLR8-TIR and a TIR of signaling adaptors, such as myeloid differentiation factor 88 (MyD88) and TIR-domain-containing adaptor-inducing interferon-β, in relation to each other according to a particular orientation forming a dimeric scaffold of their TIRs (Miyake et al. 2016). This results in the activation of transcription factors such as NF-κB, mitogen-activated protein kinases, interferon regulatory factor3 (IRF3), and IRF7.

Single Nucleotide Polymorphisms of TLR8

Intracellular TLRs have been under stronger purifying selection, because viral infections have exerted a stronger evolutionary pressure compared to bacterial infections during human evolution (Netea et al. 2012).

TLR8-129C/+1A polymorphism is significantly higher in male patients with HCV infection (Wang et al. 2014a). TLR8 expression in CD14+ cells, from volunteers with TLR8-129G/+1G, was significantly higher and showed higher interleukin-12p40 production than that derived from TLR8-129C/+1A. Nine SNPs in TLR1, TLR4, TLR6, and TLR8 in Caucasians, and two other SNPs, one each in TLR4 and TLR8, in African Americans, have been significantly associated with HIV status (Willie et al. 2014). TLR8 mRNA expression is significantly increased in HIV-infected subjects, where HIV ssRNA upregulates TLR8 expression affecting HIV pathogenesis. The TLR rs3764880 (1A>G) 1G allele displays impaired NF-kB activation and it is significantly associated with reduced disease progression.

TLR8 senses bacterial RNA released within the phagosomal vacuole and cross talk with other endosomal TLRs (Cervantes et al. 2013). Much research describing SNPs within TLR8 and their association with Mycobacterium tuberculosis (Mtb) infection. TLR8 SNPs conferred susceptibility to pulmonary TB in males of an Indonesian and Russian population (Davila et al. 2008; Thada et al. 2013) so as among male Turkish children (Dalgic et al. 2011). Four TLR8 polymorphisms have been associated to pulmonary TB susceptibility across different populations and gender. SNPs, rs3764879, rs3788935, and rs3761624, localize 5 kbp upstream of the TLR8 gene regulatory region. The minor A allele rs3764880 has shown strong susceptibility to pulmonary TB in males (Dalgic et al. 2011). In South Africa, associations with TB susceptibility were noted for TLR8 rs3764879 and TLR8 rs3764880 SNPs in both males and females, while the TLR8 rs3761624 SNP was associated with TB in females only (Salie et al. 2015). Interestingly, the associations observed for TLR8 were found to have opposite effects in males and females, where the G allele of rs3764879 and the G allele of rs3764880 were found to increase the risk of developing TB in females, while lowering it in males. The C allele of rs3764879 and A allele of rs3764880, which increase the risk for developing TB, are the minor alleles in Asian populations and the major alleles in African and European populations. The frequency of TLR8 rs3764879 CC genotype resulted significantly higher in the TB group than in controls in Chinese (Wu et al. 2015). Mutant genotype GG or G/- and G allele was significantly higher among all cases than in controls and showed a greater bacterial load (Bukhari et al. 2015). A recent meta-analysis study suggested significant associations between pulmonary TB and TLR8 rs3761624, rs3764879, rs3761624, and rs3764880 polymorphisms; TLR8 rs3788935C allele was protective (Sun et al. 2015). A meta-analysis (Schurz et al. 2015) analyzed TLR8 SNPs rs3764879 and rs3764880 in a sex-stratified manner, which resulted with no associations identified across the populations with regard to TB susceptibility (Schurz et al. 2015).

TLR8 rs3761624 SNP, localized in the p53 response element of the TLR8 promoter region, thus may alter the cells’ ability to respond to acute and chronic DNA damage stress. SNP rs3764880 disrupts TLR8 alternative transcript variant 2 (TLR8v2) and may alter the signal peptide of the TLR8 protein. Also, TLR8 transcription factor binding sites (TFBS) may be altered by the presence of the rs3764879, rs3764880, and rs3761224 polymorphisms (Salie et al. 2015).

The haplotype of TLR7 rs3853839-G and TLR8 rs3764880-G has been associated with increased risk of systemic lupus erythematosus (SLE) in females in a Taiwanese population (Wang et al. 2014b). Meta-analysis of all TLRs associated with systemic lupus erythematosus (SLE) has shown that along with TLR7 and TLR9, TLR8 polymorphisms are associated with the development of SLE in Caucasian, Asian, and African populations (Song and Lee 2016).

Although SNPs in TLR7 and TLR8 genes have shown no association with asthma susceptibility, they were associated with eosinophil counts, serum IgE level, lung function, and asthma severity (Zhang et al. 2015). TLR8 rs3764880 has been found to be associated with susceptibility to ischemic stroke (IS), IL-8, and cholesterol and LDL levels in male Chinese (Gu et al. 2016).

TLR8 activation promotes acute myeloid leukemia (AML) differentiation but inhibits its proliferation (Ignatz-Hoover et al. 2015). TLR8 rs3764879 minor allele has been shown to be significantly associated with disease-free survival after allogeneic hematopoietic cell transplantation (Kornblit et al. 2015).

TLR8 SNP rs3764880 modulates translation of the two TLR8 main isoforms, without affecting their function (Gantier et al. 2010). TLR8 variant 2 (TLR8v2) is the predominant TLR8 isoform in circulating monocytes and the prevalent form of TLR8 contributing to TLR8 function. The TLR8 long isoform (TLR8v1) is a positive regulator of TLR8 function in CD161CD141 monocytes (Gantier et al. 2010).

Endosomal TLR8 Trafficking by UNC93B1

The endosomal environment allows TLR8 and its ligand to form a more stable complex at pH5.5, where they can target late endosome and lysosomes, which have a pH5 (Lee et al. 2012). In the endosome TLR8 is converted to its mature forms by pH-dependent endosomal cathepsins and furin-like proprotein convertase (Ishii et al. 2014). TLR8 localizes to early endosomes and the endoplasmic reticulum (ER) but not to the late endosome or lysosome in human monocytes and HeLa transfectants (Itoh et al. 2011). The ER-resident membrane protein UNC93B1 physically associates with endosomal TLRs and delivers them from the ER to endolysosomes, where they become activated after encounter with their ligands. A differential sorting of endosomal TLRs by UNC93B1 has been described (Lee et al. 2013). UNC93B1 plays a critical role in TLR8-mediated signaling (Itoh et al. 2011). Hence mutations in UNC93B1 lead to an abnormal response to TLR stimulation (Conley 2007). Major endocytic adaptor protein complexes AP1 and AP2 are crucial for UNC93B1 trafficking but are dispensable for human endosomal TLR responses (Pelka et al. 2014).

Signaling Pathways and Clinical Significance of TLR8

Activation of TLR8 leads to recruitment of TLR adaptor MyD88 leading to NF-κB or IRF7 translocation into the nucleus (Kawasaki and Kawai 2014). AP1 and NF-κB induce proinflammatory cytokines such as IL-1, IL-6, IL-12, and TNF-α. Stimulation of TLR8 induces IRF7 leading to production of type I IFNs (Cervantes et al. 2013; Gosu et al. 2012; Bergstrom et al. 2015) (Fig. 2).
TLR8, Fig. 2

MyD-88-dependent TLR8 signaling pathway is initiated by ligand binding

Despite their similarities, TLR7 and TLR8 trigger different signaling pathways. This is well exemplified in dendritic cells where TLR7 and TLR8 activation leads to upregulation of receptors like CCR7, CD40, CD86, and CD83 and IL-6 and IL-12p40 production, but only TLR8 activation leads to IL-12p70 production and il-12p35 mRNA expression. p38MAPK participates in the upregulation of maturation markers in response to TLR7 activation, but it exerts an inhibitory effect on CD40 expression and IL-12 production in TLR8-stimulated DCs. Jak/STAT signaling pathway is involved in CD40 expression and cytokine production in TLR7-stimulated DCs but negatively regulated CD83 expression and cytokine secretion in DCs activated through TLR8 (Larange et al. 2009).

Sensing of UR/URR motifs in bacterial RNA by TLR8 (Kruger et al. 2015) induces the production of NF-κB-dependent cytokines, and also of type I IFN, IFN-β (Cervantes et al. 2013; Bergstrom et al. 2015), in a process that depends on lysosomal maturation (Eigenbrod et al. 2015). TLR8 bacterial RNA recognition appears to be important in the severity of Lyme disease (Cervantes et al. 2011; Cervantes et al. 2012). TLR8 is involved in the recognition of Mtb (Bruns and Stenger 2014) and controls apoptosis of human monocytes upon infection with bacillus Calmette-Guerin (BCG) (Tang et al. 2016). Interferon-α (IFN-α) enhances the production of IL-1 by human neutrophils in a TLR8-dependent manner (Zimmermann et al. 2016). TLR8 is involved in priming of human neutrophil reactive oxygen species (ROS) production (Makni-Maalej et al. 2015).

TLR8 and TLR7 inhibit hepatitis B virus translocation across the placenta, preventing intrauterine transmission (Tian et al. 2015). Clearance of human papillomavirus (HPV) 16 and 51 are associated with increased expression of all endosomal TLRs (TLR3, TLR7, TLR8, and TLR9), as with concomitant changes in INF-α2 levels (Daud et al. 2011). On the other hand, overexpression of TLR7/8 may be detrimental. TLR8 and TLR7 are highly expressed in lung and brain tissue of death caused by enterovirus type 71 (EV71) (Li et al. 2015).

TLR8 inhibits TLR7 and TLR9 (Wang et al. 2006; Paul et al. 2016). Deletion of TLR8 accelerates autoimmune disease in a mouse model for SLE, through a TLR7-dependent mechanism (Tran et al. 2015; Demaria et al. 2010). TLR8 is also expressed on human TRegs (Peng et al. 2005).

Along with other endosomal TLRs (TLR7 and TLR9), TLR8 has been associated with asthma exacerbations (Papaioannou et al. 2016). This opens new therapeutic possibilities aimed to control asthmatic inflammation. TLR8 agonists are also being tested for their use in immunotherapy, an emerging modality for the treatment of cancer (Kaczanowska et al. 2013).

Summary

Because the murine TLR8 was considered for long time inactive, we have seen a great amount of discoveries in the functions of TLR8 in the immune response to RNA recognition. Current knowledge evidences the versatility of TLR8 in infectious, inflammatory, and autoimmune diseases. TLR8 plays a pivotal role in the regulation of mouse TLR7 expression and prevention of spontaneous autoimmunity. Due to its interaction with other TLRs, new avenues for the treatment of cervical HPV persistence and use of TLR8 agonists as immunotherapy to treat cancer begin to emerge.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Jorge L. Cervantes
    • 1
  • Nancy Maulén
    • 2
  • Han-Ha Chai
    • 3
  1. 1.Paul L. Foster School of MedicineTexas Tech University Health Sciences CenterEl PasoUSA
  2. 2.Laboratorio ClínicoHospital Félix Bulnes CerdaSantiagoChile
  3. 3.National Institute of Animal Science, RDAWanju, Jeollabuk-doKorea