TLR8: A Closer Look at Its Role in Human Inflammation

Toll-like receptor 8 (TLR8) is a key component of the innate immune system, detecting pathogens and initiating inflammatory responses. It primarily recognizes single-stranded RNA (ssRNA) from viruses and microbes, triggering signaling pathways that lead to cytokine production. Given its role in immune defense, TLR8 has been studied for its involvement in both protective immunity and pathological inflammation.

Structural Features

TLR8 is a transmembrane protein in the Toll-like receptor family, featuring a leucine-rich repeat (LRR) ectodomain, a single transmembrane helix, and a cytoplasmic Toll/IL-1 receptor (TIR) domain. The LRR ectodomain, responsible for ligand recognition, consists of repeating units forming a horseshoe-shaped solenoid structure. This conformation facilitates binding to ssRNA, its primary ligand. X-ray crystallography studies show that ligand binding induces a conformational shift, promoting receptor dimerization, which is essential for signaling activation.

Unlike some Toll-like receptors requiring accessory proteins for ligand recognition, TLR8 undergoes a direct conformational change upon ssRNA binding. This rearrangement brings the intracellular TIR domains of two TLR8 monomers into proximity, enabling the recruitment of adaptor proteins for signal transduction. Specific residues within the ectodomain stabilize the dimer interface, influencing ligand affinity and receptor responsiveness.

The intracellular TIR domain shares a conserved fold with other Toll-like receptors, consisting of five β-strands surrounded by α-helices. This domain interacts with downstream signaling molecules, primarily MyD88, through a BB-loop motif. Mutations in this region disrupt signal propagation, underscoring the importance of precise molecular interactions. Post-translational modifications such as ubiquitination and phosphorylation regulate TIR domain activity, fine-tuning receptor function.

Role in Innate Immune Signaling

TLR8 detects foreign RNA molecules and initiates intracellular signaling cascades. Unlike surface-expressed Toll-like receptors, TLR8 is localized in endosomal compartments, where it surveys internalized material for microbial signatures. Its endosomal restriction helps prevent aberrant activation by host-derived RNA.

Upon encountering ssRNA, TLR8 undergoes dimerization, triggering a signaling cascade mediated by MyD88. The cytoplasmic TIR domains recruit MyD88, forming a Myddosome complex that includes IRAK-4 and IRAK-1. Phosphorylation of these kinases activates TRAF6, an E3 ubiquitin ligase that modifies key signaling intermediates, leading to activation of the TAK1 kinase complex.

TAK1 directs TLR8-induced signaling toward nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinases (MAPKs). NF-κB activation occurs through IκB phosphorylation and degradation, allowing NF-κB to translocate to the nucleus and initiate inflammatory gene transcription. Concurrently, MAPKs such as p38, JNK, and ERK enhance cytokine production, amplifying the inflammatory response.

Recognition Mechanisms

TLR8 identifies ssRNA through a structural framework that prioritizes specificity while remaining adaptable to diverse pathogenic sequences. Recognition is influenced by nucleotide composition, secondary structure, and chemical modifications. Unlike double-stranded RNA sensors, TLR8 preferentially binds short ssRNA fragments rich in uridine and guanosine. Biochemical assays confirm that RNA oligonucleotides with high uridine content elicit stronger receptor activation.

Crystallographic studies reveal that TLR8 accommodates ssRNA within a binding pocket formed by its LRR ectodomain. Conserved residues interact with the phosphate backbone and nucleobases, stabilizing the RNA. Ligand binding induces cooperative interactions between two receptor molecules, ensuring that only appropriate RNA sequences trigger activation.

RNA modifications also influence TLR8 recognition. Methylation patterns and base modifications affect receptor engagement. Some viral RNAs evade detection through 2’-O-methylation, while bacterial RNA, lacking extensive modifications, is more immunostimulatory. This dynamic interaction highlights the evolutionary arms race between host immunity and microbial evasion strategies.

Expression in Human Cells

TLR8 is highly expressed in myeloid-derived immune cells, including monocytes, macrophages, and dendritic cells, where it resides in endosomal compartments. Post-translational modifications and trafficking mechanisms regulate its intracellular localization. While primarily found in immune cells, certain epithelial and stromal cells also express TLR8 under specific conditions, though at lower levels.

Expression levels fluctuate in response to inflammatory stimuli, microbial exposure, and cellular differentiation. Pro-inflammatory cytokines like interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) enhance TLR8 transcription in monocytes and macrophages, while microRNAs and epigenetic modifications can suppress expression to prevent excessive activation. This regulatory balance is particularly crucial in tissues such as the gut and lungs, where dysregulated expression is linked to disease.

Cross-Talk with Other Receptors

TLR8 interacts with other pattern recognition receptors to fine-tune immune responses. Among these, its relationship with TLR7 is notable due to their structural similarity and shared recognition of ssRNA. While both are endosomally localized, TLR8 responds more strongly to bacterial RNA, whereas TLR7 is more sensitive to viral RNA. Knockout models show that the absence of one receptor does not fully compensate for the other, highlighting their complementary roles.

Beyond TLR family members, TLR8 interfaces with cytosolic RNA sensors such as RIG-I and MDA5, which detect viral RNA and activate antiviral defenses. This interplay is particularly evident in viral infections, where simultaneous activation of both pathways strengthens the inflammatory response. TLR8 signaling also influences NOD-like receptor (NLR) activity, modulating inflammasome assembly and cytokine release. This interconnected network ensures immune responses are appropriately scaled to prevent excessive inflammation.

Association with Inflammatory Conditions

Dysregulated TLR8 activation is linked to autoimmune diseases, chronic inflammatory disorders, and cancer. In systemic lupus erythematosus (SLE), aberrant TLR8 signaling contributes to self-RNA recognition, leading to sustained immune activation and tissue damage. Elevated TLR8 expression in monocytes and dendritic cells correlates with increased pro-inflammatory cytokines, suggesting its role in immune tolerance breakdown.

In chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, excessive TLR8 activation exacerbates tissue destruction through cytokine release. Conversely, TLR8 has been explored as a therapeutic target in oncology, where its activation can enhance anti-tumor immunity. Some cancer cells manipulate this pathway to evade immune surveillance, while TLR8 agonists are being investigated to boost immune responses against tumors.

Genetic Variations

Genetic variations in TLR8 influence immune responses, with single nucleotide polymorphisms (SNPs) altering receptor function. Certain SNPs, such as rs3764880, result in amino acid substitutions that enhance receptor activity, leading to heightened cytokine production. Carriers of these polymorphisms exhibit stronger immune responses to infections, which can aid pathogen clearance but also contribute to inflammatory diseases.

Loss-of-function mutations in TLR8 are associated with increased susceptibility to tuberculosis and other intracellular infections. These mutations impair microbial RNA recognition, reducing inflammatory mediator production. Population studies show that TLR8 polymorphisms vary across ethnic groups, suggesting evolutionary pressures have shaped genetic variation to optimize immune responses to region-specific pathogens. Understanding these genetic influences provides insights into disease risk and potential therapeutic strategies.