Toll-like receptor 8

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). This wide distribution makes TLRs an excellent tool for both the innate and the 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.

The natural ligand for the dimeric receptor TLR7/TLR8 is single-stranded RNA (ssRNA), as it occurs in viruses, but also in human cells or in the form of so-called synthetic oligoribonucleotides (ORN). Apparently, this recognition is motif-dependent (Hornung V et al. 2008). While long ssRNA is easily recognized by TLR7 and TLR8, the recognition of short RNA oligonucleotides only seems to work reliably if certain sequence motifs for TLR7 and TLR8, so-called "is RNA = immunostimulatory RNA", are present.

Extracellular ssRNA is only present if the body's own or foreign cells have perished. In either case, this condition is evaluated by the immune system as a danger signal. Extracellular ssRNA is recognized via TLR7/TLR8 and an inflammatory reaction is triggered.

Keratinocytes express several TLRs. This fact has improved our understanding of the pathogenesis of psoriasis. For example, TLR9-activated keratinocytes secrete type 1 interferons. Antagonists of TLR7 and TLR8 as well as anti-IL-12/IL-23 antibodies show good clinical therapeutic results in this disease (Rahmani F et al. 2016).

Several TLR agonists are in clinical or preclinical trials for the indications bronchial asthma or allergic rhinosinusitis (CRX-675:TLR4 agonist; AZD8848: TLR7 agonist; VTX-1463:TLR8 agonist, 1018 ISS and QbG10:TLR9 agonists - Horak F 2011; Aryan Z et al.2015)

The rationale for this therapeutic approach A is the realization that TLR agonists reduce the allergen-triggered Th2 immune response and thus the hyperresponsiveness of the respiratory mucosa.

• A heterozygous pathogenic variant con c.1715G>A (pGly572Asp) in the Toll-like receptor 8 gene has been described with lethal congenital immunodeficiency.
• Toll-like receptor 8 deficiency syndrome: In 6 unrelated males with neutropenia, infections, lymphoproliferation, humoral immunodeficiencies and in some cases bone marrow failure associated with 3 different variants in the X-linked gene TLR8 encoding the endosomal Toll-like receptor 8 (TLR8). 5 patients had somatic variants in TLR8 with <30% mosaicism, suggesting a dominant mechanism as the cause of the clinical phenotype. Mosaicism was also detected in skin fibroblasts of 3 patients, indicating that the mutations were not restricted to the hematopoietic compartment. All patients had refractory chronic neutropenia, and 3 patients underwent allogeneic hematopoietic cell transplantation. All variants resulted in a GOF (gain of function) in the TLR8 protein. Clinically, a proinflammatory phenotype with activated T cells and elevated serum cytokines associated with impaired B cell maturation was also found. Differentiation of myeloid cells from patient-derived induced pluripotent stem cells showed increased responsiveness to TLR8 (Aluri J et al. (2021).
• Another missense variant at the same amino acid exposure (8pGly572Val) led to erythema nodosum, severe autoimmune hemolytic anemia and autoinflammation, and steroid-sensitive antiphospholipid syndrome in monozygotic twins (Lkiu-JW et al. 2025).

1. Aluri J et al. (2021) Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function. Blood 137:2450-2462.

2. Aryan Z et al.(2015) Toll-like receptors as targets for allergen immunotherapy. Curr Opin Allergy Clin Immunol 15:568-574.
3. Horak F (2011) VTX-1463, a novel TLR8 agonist for the treatment of allergic rhinitis. Expert Opin Investig Drugs. 20:981-986.
4. Hornung V et al. (2008) RNA recognition via TLR7 and TLR8. Handb Exp Pharmacol 183:71-86.
5. 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. https://www.ncbi.nlm.nih.gov/pubmed/22325161
6. Liu JW et al. (2025)Toll-like receptor 8 deficiency syndrome result in diffuse pigmented skin rash and autoinflammatory syndrome. J Dtsch Dermatol Ges 23:763-765.
7. Rahmani F et al.(2016) Therapeutic targeting of Toll-like receptors: a review of Toll-like receptors and their signaling pathways in psoriasis. Expert Rev Clin Immunol 12:1289-1298. https://www.ncbi.nlm.nih.gov/pubmed/27359083
8. 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.