TLR8 - toll like receptor 8 |Elisa - Clia - Antibody - Protein

Background

Toll-like receptor 8 (TLR8) is a member of the toll-like receptor family, which plays a crucial role in the innate immune system by recognizing specific molecular patterns associated with pathogens. TLR8, in particular, is an endosomal receptor that primarily recognizes single-stranded RNA (ssRNA) from viruses and other microorganisms, making it a significant player in detecting RNA viruses, such as influenza and certain coronaviruses. As part of the pattern recognition receptor (PRR) family, TLR8 is instrumental in initiating the innate immune response upon detection of foreign RNA, leading to the production of inflammatory cytokines and antiviral responses.

TLR8 expression is largely found within immune cells, specifically in monocytes, macrophages, and dendritic cells, with notable expression in myeloid dendritic cells. Its activation is associated with the MyD88-dependent signaling pathway, which ultimately results in the production of cytokines and type I interferons (IFNs), essential mediators in controlling viral infections. TLR8’s unique role in recognizing RNA-based pathogens positions it as a potential therapeutic target for treating viral infections, certain inflammatory diseases, and possibly cancers.

Protein Structure

TLR8 is a type I transmembrane protein and shares a highly conserved structural framework with other toll-like receptors. It consists of approximately 1,040 amino acids organized into three primary domains: an extracellular domain, a transmembrane domain, and a cytoplasmic Toll/interleukin-1 receptor (TIR) domain. These domains allow TLR8 to recognize ligands, transduce signals, and initiate downstream signaling cascades effectively.

Extracellular Domain:

• The extracellular domain of TLR8 is composed of leucine-rich repeats (LRRs) that form a curved solenoid shape, enabling the receptor to interact with specific ligands. In TLR8, this domain is uniquely structured to bind ssRNA derived from pathogens.
• TLR8 functions as a monomer that recognizes ssRNA directly, and it undergoes a conformational change upon ligand binding, a feature that distinguishes it from other TLRs which often require dimerization with another TLR (such as TLR7/TLR9).
• The ssRNA binding to TLR8 initiates receptor dimerization in the endosome, where acidic conditions facilitate ligand binding. Synthetic ligands, such as imidazoquinolines, can also activate TLR8 and are used in research and potential clinical applications.

Transmembrane Domain:

• TLR8’s transmembrane domain is a single alpha-helix that anchors it to the endosomal membrane, placing it in proximity to potential viral RNA and other pathogenic nucleic acids.
• Although the transmembrane domain does not participate directly in ligand recognition, it ensures the correct orientation and stability of the receptor within the membrane, which is essential for efficient downstream signaling.

Cytoplasmic TIR Domain:

• The Toll/interleukin-1 receptor (TIR) domain of TLR8, located on the cytoplasmic side, initiates downstream signaling upon activation. This domain is responsible for recruiting the adaptor protein MyD88 (myeloid differentiation primary response 88).
• Once MyD88 is recruited, it activates a cascade involving IRAKs (IL-1 receptor-associated kinases), which leads to the activation of transcription factors like NF-κB and IRF7. This cascade culminates in the production of pro-inflammatory cytokines (e.g., TNF-α, IL-6) and type I interferons, particularly IFN-α, which are essential for antiviral responses.

Classification and Subtypes

TLR8 is part of the TLR7/8/9 subfamily within the toll-like receptor family, which includes receptors that recognize nucleic acids and are located in endosomal compartments. It is closely related to TLR7, which also detects RNA ligands, though each has specific ligand preferences and expression profiles.

There are no distinct subtypes or isoforms of TLR8, though its expression and function may vary depending on the cell type and the inflammatory environment. While TLR7 is more commonly expressed in plasmacytoid dendritic cells, TLR8 is primarily expressed in myeloid cells, such as macrophages and conventional dendritic cells, contributing to distinct yet complementary roles in pathogen recognition and immune activation.

Function and Biological Significance

TLR8 plays an essential role in the immune response by detecting single-stranded RNA from pathogens and initiating an antiviral immune response. Key functions of TLR8 include:

Pathogen Detection:

• TLR8 is specialized in recognizing ssRNA from viruses, such as influenza, HIV, and certain RNA-based coronaviruses. When ssRNA from these pathogens binds to TLR8, the receptor undergoes a conformational change and dimerizes, a critical step for signaling.
• Besides viral recognition, TLR8 is thought to participate in detecting bacterial RNA and synthetic RNA-like compounds, broadening its role in pathogen sensing. The receptor can also recognize certain endogenous RNA, which can trigger immune responses in autoimmune diseases.

Immune Activation and Inflammatory Signaling:

• Upon ligand binding, TLR8 signals through the MyD88-dependent pathway, which leads to the activation of downstream transcription factors like NF-κB and IRF7. These transcription factors drive the expression of inflammatory cytokines, including IL-6, TNF-α, and IL-12, as well as type I interferons (IFNs).
• TLR8-mediated cytokine release is critical for recruiting and activating additional immune cells, including neutrophils, macrophages, and T cells, to contain and clear infections. This activation leads to a strong pro-inflammatory response that aids in controlling viral replication.

Role in Adaptive Immunity:

• TLR8 also influences the adaptive immune response by promoting antigen presentation and dendritic cell maturation. Activation of TLR8 in dendritic cells leads to upregulation of MHC molecules and co-stimulatory factors necessary for T cell activation, enhancing the adaptive immune response against specific pathogens.
• Through cytokine production, TLR8 indirectly affects B-cell and T-cell responses, making it an important link between innate and adaptive immunity.

Self-RNA Recognition and Autoimmunity:

• TLR8 can sometimes recognize endogenous RNA from dying cells or cellular debris. This self-recognition can lead to inappropriate immune responses and chronic inflammation, contributing to autoimmune conditions.

Clinical Issues

Dysregulation of TLR8 signaling is associated with various inflammatory and autoimmune diseases, viral infections, and cancers:

Autoimmune Diseases:

• TLR8 is implicated in autoimmune diseases, such as systemic lupus erythematosus (SLE), where excessive TLR8 activation by self-RNA leads to chronic inflammation. Overactive TLR8 signaling in SLE and other autoimmune conditions drives sustained cytokine release and tissue damage.
• Rheumatoid arthritis (RA) is another condition linked to TLR8 activity, where the receptor may detect endogenous RNA released from damaged cells, perpetuating joint inflammation.

Viral Infections:

• TLR8 activation is crucial in responding to RNA viruses. However, in some cases, excessive TLR8 activity during viral infections, like influenza and COVID-19, can lead to a cytokine storm, an overproduction of inflammatory cytokines that can damage tissues.
• TLR8 agonists and antagonists are being explored as therapeutic options for controlling the immune response to specific viruses, aiming to enhance antiviral immunity while avoiding excessive inflammation.

Cancer:

• The role of TLR8 in cancer is complex. In certain tumors, TLR8 activation may promote an immune-suppressive environment that allows tumor growth, while in others, TLR8 activation can stimulate anti-tumor immunity.
• TLR8 agonists are being investigated as potential immunotherapy agents in cancers, where they may boost immune responses to target tumor cells.

Therapeutic Targeting:

• Synthetic agonists of TLR8, such as imiquimod and resiquimod, are used in research and treatment contexts to stimulate immune responses, particularly in cancers and viral infections. Antagonists are also under investigation to prevent TLR8-mediated inflammation in autoimmune and chronic inflammatory diseases.

Summary

TLR8 is a critical toll-like receptor that plays a vital role in detecting single-stranded RNA from pathogens, particularly RNA viruses, within the endosome of immune cells. Its structure, which includes an LRR-rich extracellular domain and a TIR domain for intracellular signaling, enables it to recognize viral RNA directly and initiate a potent immune response via the MyD88-dependent pathway. This response includes cytokine production and the activation of NF-κB and IRF7, which promote antiviral immunity and inflammation.

Clinically, TLR8 is involved in a range of inflammatory diseases, autoimmune conditions, and cancers. While it provides essential antiviral defenses, excessive or inappropriate activation of TLR8 can contribute to autoimmune diseases like SLE and RA. In cancer, TLR8 signaling can either promote or inhibit tumor progression depending on the context, making it a promising yet complex therapeutic target. Therapeutics aimed at modulating TLR8 activity, including agonists for boosting immunity in infections and cancers, and antagonists for reducing inflammation in autoimmune diseases, continue to be explored for their potential benefits.