TLR8

Official Full Name

toll like receptor 8

Organism

Homo sapiens

GeneID

51311

Background

The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is predominantly expressed in lung and peripheral blood leukocytes, and lies in close proximity to another family member, TLR7, on chromosome X. [provided by RefSeq, Jul 2008]

Synonyms

CD288; IMD98; TLR-8; hTLR8;

Bio Chemical Class

Toll-like receptor

Protein Sequence

MENMFLQSSMLTCIFLLISGSCELCAEENFSRSYPCDEKKQNDSVIAECSNRRLQEVPQTVGKYVTELDLSDNFITHITNESFQGLQNLTKINLNHNPNVQHQNGNPGIQSNGLNITDGAFLNLKNLRELLLEDNQLPQIPSGLPESLTELSLIQNNIYNITKEGISRLINLKNLYLAWNCYFNKVCEKTNIEDGVFETLTNLELLSLSFNSLSHVPPKLPSSLRKLFLSNTQIKYISEEDFKGLINLTLLDLSGNCPRCFNAPFPCVPCDGGASINIDRFAFQNLTQLRYLNLSSTSLRKINAAWFKNMPHLKVLDLEFNYLVGEIASGAFLTMLPRLEILDLSFNYIKGSYPQHINISRNFSKLLSLRALHLRGYVFQELREDDFQPLMQLPNLSTINLGINFIKQIDFKLFQNFSNLEIIYLSENRISPLVKDTRQSYANSSSFQRHIRKRRSTDFEFDPHSNFYHFTRPLIKPQCAAYGKALDLSLNSIFFIGPNQFENLPDIACLNLSANSNAQVLSGTEFSAIPHVKYLDLTNNRLDFDNASALTELSDLEVLDLSYNSHYFRIAGVTHHLEFIQNFTNLKVLNLSHNNIYTLTDKYNLESKSLVELVFSGNRLDILWNDDDNRYISIFKGLKNLTRLDLSLNRLKHIPNEAFLNLPASLTELHINDNMLKFFNWTLLQQFPRLELLDLRGNKLLFLTDSLSDFTSSLRTLLLSHNRISHLPSGFLSEVSSLKHLDLSSNLLKTINKSALETKTTTKLSMLELHGNPFECTCDIGDFRRWMDEHLNVKIPRLVDVICASPGDQRGKSIVSLELTTCVSDVTAVILFFFTFFITTMVMLAALAHHLFYWDVWFIYNVCLAKVKGYRSLSTSQTFYDAYISYDTKDASVTDWVINELRYHLEESRDKNVLLCLEERDWDPGLAIIDNLMQSINQSKKTVFVLTKKYAKSWNFKTAFYLALQRLMDENMDVIIFILLEPVLQHSQYLRLRQRICKSSILQWPDNPKAEGLFWQTLRNVVLTENDSRYNNMYVDSIKQY

Open

Disease

Allergic/hypersensitivity disorder, Diabetes mellitus, Diffuse large B-cell lymphoma, Epidermal dysplasias, Hepatitis virus infection, Herpes simplex infection, Lupus erythematosus, Melanoma, Mycosis fungoides, Rheumatoid arthritis, Solid tumour/cancer, Squamous cell carcinoma, Vasomotor/allergic rhinitis

Approved Drug

Clinical Trial Drug

11 +

Discontinued Drug

2 +

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Detailed Information

TLR8, located near TLR7 on the X chromosome (Xp22.2), shares significant structural similarities with TLR7 but differs in its ligand specificity. It primarily recognizes single-stranded RNA (ssRNA) rich in uridine (UR) as well as small molecules like Resiquimod. The activation of TLR8 follows a two-step mechanism: first, the endosomal RNase T2 degrades bacterial or viral RNA into shorter fragments, and then TLR8 dimerizes and recruits the adaptor protein MyD88, forming the Myddosome complex. This complex activates the NF-κB and IRF7 signaling pathways. Interestingly, Mycobacterium tuberculosis (Mtb) can directly activate TLR8 through the secretion of RNA-containing extracellular vesicles (MVs), a process that can be inhibited by RNase treatment.

Figure 1. TLR signaling overview. (Cervantes JL, et al., 2012)

TLR8 plays a pivotal role in host defense against several types of pathogens. In the case of Mycobacterium tuberculosis infection, TLR8 recognizes bacterial RNA and triggers the nuclear translocation of TFEB, enhancing phagosome-lysosome fusion. This process promotes the recruitment of autophagic proteins like NDP52 and LC3, which aid in the clearance of intracellular bacteria. CRISPR screening has shown that macrophages lacking TLR8 have a threefold increased survival rate of Mtb, underlining the receptor's essential role in bacterial clearance. In viral defense, TLR8 recognizes GU-rich RNA regions in SARS-CoV-2 and induces the secretion of IL-12 and TNF-α, leading to the activation of a Th1 immune response. Unlike TLR7, which is primarily expressed in plasmacytoid dendritic cells (pDCs), TLR8 is mostly expressed in myeloid dendritic cells (mDCs), where it is more inclined to promote pro-inflammatory cytokines rather than interferons. TLR8 is also involved in fungal and parasitic recognition; for example, the RNA of Candida albicans activates neutrophils to form neutrophil extracellular traps (NETs) via the TLR8-MyD88 signaling pathway. Similarly, TLR8 recognizes the RNA of Plasmodium, triggering macrophage secretion of IL-1β, a key cytokine in the immune response to malaria.

Abnormal activation or defects in TLR8 have been implicated in various diseases. A notable example is tuberculosis susceptibility, where the TLR8 M1V variant (rs3764880) significantly enhances macrophage killing of Mtb. Mechanistically, this variant alters the receptor's localization, leading to its enrichment in Mtb-containing phagosomes, which increases lysosomal acidification, making it more effective at killing bacteria. This variant is found at a higher frequency in East Asian populations, indicating a potential natural selection advantage in defending against tuberculosis. In cancer, high expression of TLR8 mRNA in diffuse large B-cell lymphoma (DLBCL) correlates with the degree of neutrophil infiltration and is associated with immune suppression through the upregulation of immune checkpoint molecules like LAG3 and CD274. Patients with high TLR8 expression have a significantly shorter overall survival, suggesting that TLR8 may serve as a prognostic biomarker. Additionally, gain-of-function mutations in TLR8 have been linked to autoimmune conditions such as X-linked immunodeficiency 98 (XMEN-ID98), which is characterized by neutropenia and Epstein-Barr virus-driven lymphoproliferation.

Therapeutically, TLR8 agonists have shown promise in treating infections and cancers. In tuberculosis, Resiquimod, a TLR7/8 dual agonist, has demonstrated significant potential in preclinical studies for treating multi-drug-resistant tuberculosis (MDR-TB), reducing bacterial load in mouse lungs by 99%. When used in combination with isoniazid, it has been shown to shorten treatment durations, bypassing bacterial resistance mechanisms by directly enhancing the host's immune response to kill intracellular bacteria. In cancer immunotherapy, TLR8 selective agonists like Motolimod have been shown to reverse the M2-type tumor-associated macrophage phenotype, promoting antigen presentation and improving anti-tumor immunity. In clinical trials for DLBCL, combining TLR8 agonists with anti-CD20 antibodies like Rituximab has enhanced the objective response rate, suggesting a promising approach to improving immune-mediated tumor clearance. To reduce systemic toxicity, liposomal formulations of TLR8 ligands such as VTX-2337 have been developed for targeted delivery to tumor tissues. These formulations enable localized activation of myeloid cells without triggering a systemic cytokine storm, offering a safer approach to immunotherapy.

Despite the promise of TLR8-targeted therapies, several challenges remain. One key issue is balancing immune activation with inflammation control. TLR8 activation in mDCs primarily triggers NF-κB signaling, whereas in monocytes, it activates IRF5. This difference necessitates the development of cell-type-specific agonists to fine-tune immune responses. Additionally, Mycobacterium tuberculosis has evolved mechanisms to inhibit TLR8 activation by secreting liparabinomannan (LAM), which blocks the receptor's endosomal localization. Combining TLR8 agonists with LAM inhibitors could overcome this resistance and enhance immune responses. Lastly, the TLR8 M1V variant has been shown to enhance responses to Resiquimod, suggesting that genetic profiling could play a role in optimizing therapy. Future clinical trials will need to incorporate genetic stratification to better match patients with the most effective treatments based on their genetic background.

In summary, TLR8 plays a critical role in immune defense, with diverse functions in defending against infections, regulating tumor immunity, and modulating inflammation. While TLR8-targeted therapies hold great promise for treating diseases like tuberculosis, cancer, and autoimmune disorders, significant challenges remain in optimizing these therapies. Future research will focus on developing more precise, cell-specific treatments, overcoming resistance mechanisms, and exploring personalized approaches based on genetic variability.

Reference

Martínez-Espinoza I, Guerrero-Plata A. The Relevance of TLR8 in Viral Infections. Pathogens. 2022 Jan 22;11(2):134.
Cervantes JL, Weinerman B, Basole C, et al. TLR8: the forgotten relative revindicated. Cell Mol Immunol. 2012 Nov;9(6):434-8.

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