TLR10 - toll like receptor 10 |Elisa - Clia - Antibody - Protein

Background

Toll-like receptor 10 (TLR10) is the only human TLR with an entirely unknown ligand and functional role, marking it as a unique and enigmatic member of the Toll-like receptor (TLR) family. This family plays essential roles in innate immunity by recognizing pathogen-associated molecular patterns (PAMPs) and initiating immune responses. Despite its unclear ligand specificity, TLR10 is hypothesized to play regulatory roles, particularly in modulating immune responses. In humans, TLR10 is primarily expressed in lymphoid tissues such as the spleen, lymph nodes, tonsils, and the immune cells within these tissues, including B cells, dendritic cells (DCs), and monocytes. TLR10 is expressed alongside TLRs that typically recognize nucleic acids or microbial components, which suggests that it may function in coordination with other TLRs to fine-tune immune responses, potentially acting as a regulatory or inhibitory receptor.

Protein Structure

Structurally, TLR10 resembles other TLR family members, with unique features and slight variations that likely influence its regulatory roles. TLR10 has three main structural domains:

Extracellular Domain:

• TLR10’s extracellular domain, like other TLRs, consists of leucine-rich repeats (LRRs) that form a solenoid structure, or horseshoe-like shape. This LRR domain is crucial for ligand binding, though the specific ligand for TLR10 remains unidentified.
• Each LRR motif contains conserved and variable regions that are responsible for maintaining structure and potentially binding molecules. Although TLR10 is believed to be involved in immune modulation, the lack of a known ligand has limited a detailed understanding of how the LRR domain specifically engages with potential ligands.
• Structural analyses reveal that TLR10 can form homodimers, a common structural configuration for TLRs involved in signal transduction. However, this dimerization may serve functions beyond direct pathogen recognition, potentially facilitating cross-talk with other receptors or acting in a ligand-independent manner to exert regulatory control.

Transmembrane Domain:

• TLR10 contains a single alpha-helical transmembrane domain that anchors it to the cell membrane. Unlike other TLRs that may be found on the cell surface or within endosomal compartments, TLR10 is predominantly localized to the cell membrane.
• The transmembrane region likely stabilizes the receptor, allowing it to interact with other receptors or signaling molecules, and could potentially mediate cross-linking with TLR2, a receptor it can dimerize with.

Cytoplasmic Toll/Interleukin-1 Receptor (TIR) Domain:

• The cytoplasmic TIR domain is essential for intracellular signaling. In TLR10, this domain is highly conserved, allowing it to associate with TLR-specific adaptor molecules.
• TLR10’s TIR domain is capable of interacting with MyD88, a key adaptor molecule used by many TLRs, but evidence suggests that TLR10 may use MyD88 in a unique way, potentially suppressing inflammatory responses rather than activating them. This unique signaling approach may provide a way for TLR10 to counterbalance immune responses, contributing to its hypothesized inhibitory or regulatory role.

Classification and Subtypes

TLR10 is classified within the TLR1 subfamily, which also includes TLR1, TLR2, and TLR6. This subfamily is known for its ability to recognize microbial components such as lipopeptides and other lipid-containing molecules. Despite being part of this family, TLR10 lacks a defined ligand and has structural and functional distinctions that set it apart:

• Dimerization: TLR10 can form heterodimers with TLR2, suggesting potential interactions with lipopeptide ligands that TLR2 typically recognizes. However, it is likely that TLR10 may modulate the immune response induced by TLR2, possibly by dampening inflammatory signaling pathways.
• Functional Divergence: While TLR1, TLR2, and TLR6 play active roles in recognizing bacterial lipoproteins and activating immune responses, TLR10 is speculated to act as an anti-inflammatory regulator, positioning it as a unique member of the TLR1 subfamily with a distinct function focused on modulating rather than directly initiating immune responses.

Function and Biological Significance

Although its precise function is still under investigation, evidence suggests that TLR10 serves as a modulator of immune responses, likely with inhibitory effects. Some of the key functions and potential biological roles of TLR10 include:

Immune Modulation and Anti-inflammatory Role:

• Research indicates that TLR10 might act as an inhibitory receptor in immune responses, a function that would make it unique among the TLR family. Studies have shown that TLR10 can suppress pro-inflammatory cytokine production when co-expressed with other TLRs, suggesting that it may counterbalance TLR-mediated immune activation.
• TLR10 can negatively regulate NF-κB and MAPK signaling pathways, which are essential for cytokine production and immune cell activation. This regulatory capacity points to TLR10’s potential role in preventing excessive inflammation that could otherwise lead to tissue damage.

Role in B Cells:

• TLR10 is highly expressed in B cells, indicating a specialized role in modulating B cell functions, including antibody production and class switching. By fine-tuning the immune response in B cells, TLR10 could influence adaptive immunity and potentially prevent autoimmunity by controlling B cell activation thresholds.
• In B cells, TLR10 signaling may contribute to immune tolerance, preventing overactivation in response to self-antigens or commensal microorganisms.

Interaction with TLR2:

• TLR10 can form heterodimers with TLR2, which is known for recognizing bacterial lipopeptides. While the TLR2-TLR10 heterodimer’s specific functions are not fully characterized, it may serve to modulate TLR2 signaling pathways.
• By interacting with TLR2, TLR10 may influence immune responses to bacterial infections, potentially mitigating inflammatory responses when pathogens are controlled or low-grade infections occur.

Potential Role in Infection and Tolerance:

• TLR10 may play a protective role in chronic infections or situations where excessive inflammation would be harmful, such as in the gut or other mucosal surfaces. Its expression in immune-rich tissues suggests that TLR10 could serve as a regulatory checkpoint, especially in areas frequently exposed to pathogens.

Clinical Issues

TLR10’s potential regulatory role makes it a promising target for therapeutic modulation in diseases characterized by excessive inflammation or immune dysregulation:

Autoimmune Diseases:

• Given its inhibitory function, TLR10 could serve as a target in autoimmune conditions where immune tolerance is compromised. Enhancing TLR10 activity might help reduce autoimmune responses, potentially benefiting conditions like rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE).

Chronic Inflammatory Conditions:

• In diseases associated with chronic inflammation, such as inflammatory bowel disease (IBD) and asthma, TLR10 may play a role in modulating inflammatory responses. Targeting TLR10 could reduce inflammation in these conditions by decreasing pro-inflammatory cytokine production, which could have therapeutic value in managing chronic inflammation.

Cancer:

• TLR10 expression in B cells and its anti-inflammatory function suggest that it may influence tumor immunity, particularly in cancers where chronic inflammation supports tumor growth and immune evasion. Inhibiting TLR10 might enhance the immune system’s ability to attack tumors by increasing immune activity, whereas activating TLR10 could help suppress inflammatory microenvironments that support tumor progression.
• Cancer immunotherapies targeting TLR10 could be developed to either enhance or dampen immune responses, depending on the type of cancer and the immune context within the tumor microenvironment.

Infectious Diseases:

• In infectious diseases, particularly chronic or latent infections, TLR10’s role in dampening immune responses might help control the immune response to avoid tissue damage. However, pathogens that exploit immune inhibition might leverage TLR10 activity to evade immune clearance. Therapies targeting TLR10 could, therefore, have dual applications in either enhancing immune response for pathogen clearance or reducing immune activation to prevent tissue damage.

Summary

TLR10, part of the Toll-like receptor family, is unique in its lack of a known ligand and apparent role as a modulatory receptor. Its protein structure is similar to other TLRs, with leucine-rich repeats for potential ligand binding, a transmembrane domain, and a conserved cytoplasmic TIR domain that transduces signals. TLR10’s structural ability to form dimers with TLR2 hints at its regulatory capabilities, while its dominant expression in immune cells, particularly B cells, aligns with its hypothesized role in immune modulation.

Functionally, TLR10 is suspected to play an anti-inflammatory role, potentially suppressing NF-κB and MAPK signaling pathways that lead to cytokine production. This characteristic positions TLR10 as a potential therapeutic target in conditions where immune modulation is required, including autoimmune diseases, chronic inflammatory conditions, and certain cancers. Its regulatory function, especially in B cells, suggests TLR10 may act to fine-tune adaptive immune responses, possibly maintaining immune tolerance and preventing excessive inflammation.

In summary, while TLR10’s ligand remains unidentified, its suspected inhibitory function makes it an intriguing target for therapeutic exploration, with promising applications in autoimmune disease, chronic inflammation, infection tolerance, and cancer therapy.