TLR6 - toll like receptor 6 |Elisa - Clia - Antibody - Protein

Background

Toll-like receptor 6 (TLR6) is a pattern-recognition receptor (PRR) in the toll-like receptor family that plays a critical role in the innate immune system. It is highly conserved across many species and primarily recognizes microbial components, particularly diacylated lipopeptides, which are lipid molecules derived from pathogens such as Gram-positive bacteria and certain fungi. TLR6 forms heterodimers with TLR2 to recognize these microbial products, allowing the immune system to detect the presence of pathogens and initiate a rapid immune response.

TLR6 is expressed in various immune cells, including macrophages, dendritic cells, monocytes, neutrophils, and certain epithelial cells. Activation of TLR6 initiates downstream signaling cascades that promote the production of pro-inflammatory cytokines and chemokines, thereby coordinating immune responses and recruiting additional immune cells to the site of infection. This receptor also plays a role in tissue repair, and recent studies suggest its involvement in some chronic inflammatory and autoimmune diseases, as well as potential links to cancer. Understanding TLR6’s mechanisms and structure is essential for designing therapeutics that can modulate immune responses in a range of diseases.

Protein Structure

TLR6, like other toll-like receptors, is a type I transmembrane protein with approximately 796 amino acids. It is structurally organized into three primary domains: an extracellular domain, a transmembrane domain, and an intracellular Toll/IL-1 receptor (TIR) domain. Each of these domains has distinct structural features that contribute to TLR6’s functional capabilities.

Extracellular Domain:

• The extracellular region of TLR6 contains leucine-rich repeat (LRR) motifs, which form a horseshoe-shaped solenoid structure. This domain is responsible for ligand recognition and binding.
• TLR6 typically functions by forming a heterodimer with TLR2. This TLR2/6 heterodimer is essential for recognizing diacylated lipopeptides from pathogens. The LRR motifs in the extracellular domain are essential for this ligand-binding process, as they stabilize the binding of diacylated lipopeptides to the TLR2/6 complex.
• Unlike TLR4, TLR6 does not directly recognize lipopolysaccharides (LPS) but is instead specialized for lipid-based components from different microbial sources. The TLR6 extracellular domain interacts with co-receptors such as CD36 to enhance the response to bacterial lipopeptides, improving ligand specificity and sensitivity.

Transmembrane Domain:

• TLR6’s transmembrane domain consists of a single alpha-helical structure that anchors the receptor in the cell membrane. This domain helps maintain the proper orientation of TLR6 within the membrane, facilitating interactions with extracellular ligands and intracellular signaling molecules.
• While not directly involved in ligand recognition, the transmembrane domain plays a key role in stabilizing the receptor complex and enabling its signaling function upon activation.

Intracellular (TIR) Domain:

• The TIR (Toll/interleukin-1 receptor) domain is located in the cytoplasmic portion of TLR6 and is responsible for initiating downstream signaling once the receptor is activated. This domain contains specific sites for interaction with adaptor proteins, including MyD88.
• Upon ligand recognition and dimerization with TLR2, the TIR domain recruits MyD88, an adaptor molecule that links TLR6 to downstream kinases, such as IRAKs (IL-1 receptor-associated kinases), leading to the activation of NF-κB and MAP kinase pathways. These pathways drive the production of pro-inflammatory cytokines, such as IL-6, TNF-α, and IL-1β.
• The TIR domain also interacts with TRAF6, which plays a crucial role in transducing the signal and amplifying the immune response, facilitating a rapid defense against pathogens.

Classification and Subtypes

TLR6 is classified within the toll-like receptor (TLR) family, specifically as part of the TLR1 subfamily due to its sequence similarity and functional interactions with TLR2. TLR6 does not have subtypes or isoforms with distinct functions but relies on its ability to form heterodimers, primarily with TLR2, to recognize specific pathogen-associated molecular patterns (PAMPs). In the presence of diacylated lipopeptides, TLR6 preferentially partners with TLR2 rather than TLR1, allowing it to detect a different subset of microbial molecules compared to the TLR2/TLR1 heterodimer, which generally binds triacylated lipopeptides.

Function and Biological Significance

TLR6 plays an essential role in detecting bacterial and fungal infections by recognizing components specific to these pathogens. Its functions include:

Pathogen Recognition:

• TLR6, in complex with TLR2, recognizes diacylated lipopeptides from Gram-positive bacteria and mycoplasma. Upon ligand binding, TLR6/TLR2 heterodimers initiate signaling cascades that result in the release of pro-inflammatory cytokines and chemokines.
• This recognition process is facilitated by co-receptors like CD36, which helps TLR6 to detect a broader array of lipid-based microbial components. CD36 enhances TLR6’s sensitivity to pathogen-derived molecules, improving the immune response.

Signaling Pathways:

• TLR6 signaling predominantly activates the MyD88-dependent pathway, leading to the activation of transcription factors such as NF-κB and AP-1. These transcription factors control the expression of genes involved in inflammation, including cytokines, chemokines, and antimicrobial peptides.
• The MyD88-dependent pathway also stimulates the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), enhancing pathogen-killing capabilities.

Role in Inflammation and Immune Response:

• By activating inflammatory cytokines, TLR6 recruits and activates immune cells, such as neutrophils, macrophages, and dendritic cells, which are essential for clearing infections. This pro-inflammatory role makes TLR6 crucial in the early stages of infection and provides an initial line of defense.
• Beyond innate immunity, TLR6 activation also influences adaptive immune responses by promoting dendritic cell maturation and antigen presentation, which are key to activating T cells and shaping the immune response against specific pathogens.

Homeostasis and Tissue Repair:

• TLR6 is involved in tissue repair processes, particularly in the lung, where it helps regulate inflammatory responses during tissue injury. Proper control of TLR6 signaling in non-infectious contexts is critical to avoid excessive inflammation, which can lead to tissue damage.

Clinical Issues

Dysregulation of TLR6 signaling can lead to various clinical issues due to either excessive or insufficient immune responses:

Chronic Inflammatory Diseases:

• Overactivation of TLR6 is implicated in chronic inflammatory diseases, such as asthma and allergic responses. TLR6 expression in airway epithelial cells contributes to hyper-responsiveness and inflammation in asthma, and excessive TLR6 signaling in response to airborne allergens can exacerbate the condition.
• In conditions such as atherosclerosis, TLR6-mediated inflammation can contribute to plaque formation in arteries. By recognizing endogenous ligands, TLR6 may exacerbate vascular inflammation, worsening cardiovascular disease.

Autoimmune Disorders:

• TLR6 activation by endogenous ligands can contribute to autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In these conditions, inappropriate activation of TLR6 leads to chronic inflammation and autoimmunity, damaging healthy tissues.

Cancer:

• TLR6’s role in cancer is complex and context-dependent. In some cancers, such as breast cancer, TLR6 activation appears to promote tumor growth by modulating immune responses in the tumor microenvironment. TLR6 signaling can attract immune cells that create a pro-tumor environment, allowing cancer cells to evade immune surveillance.
• Conversely, TLR6 can also stimulate anti-tumor immune responses under certain conditions. Therapeutic targeting of TLR6 signaling in cancer is being explored as a way to shift the immune balance toward anti-tumor immunity.

Therapeutic Targeting:

• TLR6 is a potential target for therapies aimed at modulating immune responses. TLR6 inhibitors are being studied for their potential to reduce inflammation in chronic inflammatory and autoimmune diseases, while TLR6 agonists may serve as vaccine adjuvants to boost immunity against specific infections.

Summary

TLR6 is a critical component of the innate immune system, with a specific role in detecting diacylated lipopeptides from Gram-positive bacteria and fungi through heterodimer formation with TLR2. Its structure, which includes an LRR-rich extracellular domain for ligand recognition and a TIR domain for intracellular signaling, enables it to initiate a robust immune response by activating the MyD88-dependent pathway. This pathway triggers pro-inflammatory signaling cascades, including the activation of NF-κB and MAP kinase pathways, leading to cytokine production and recruitment of immune cells.

Clinically, TLR6 is involved in various inflammatory diseases, autoimmune disorders, and cancer. Dysregulated TLR6 signaling can exacerbate conditions like asthma, cardiovascular disease, and autoimmune pathologies, while in cancer, it may either support or inhibit tumor progression, depending on the context. TLR6 remains a promising therapeutic target, with research focusing on manipulating its signaling pathways to control inflammation, enhance immunity, and potentially treat cancers.