TLR2 - toll like receptor 2 |Elisa - Clia - Antibody - Protein

Background

Toll-like receptor 2 (TLR2) is an essential component of the innate immune system, known for its role in recognizing and responding to pathogen-associated molecular patterns (PAMPs). TLR2 is part of the toll-like receptor (TLR) family, which detects structural components specific to pathogens and activates immune responses. TLR2 is particularly versatile, recognizing a broad array of ligands from bacteria, fungi, and viruses, and functions primarily by forming heterodimers with other TLRs, specifically TLR1 and TLR6. These heterodimers expand TLR2’s range of ligand recognition, including lipoproteins, lipopeptides, peptidoglycan, and lipoteichoic acid, enabling it to respond effectively to both Gram-positive and Gram-negative bacteria.

The expression of TLR2 is predominantly found in immune cells such as macrophages, dendritic cells, and monocytes. TLR2’s activity is integral to the initiation of pro-inflammatory responses that support early immune defense. As such, it plays a pivotal role in the development of both innate and adaptive immunity by bridging the two responses through cytokine release and antigen presentation. Due to its broad functionality and critical role in immunity, TLR2 has become a focus for research into infections, inflammation, and immune-related diseases, as well as a potential target for immunotherapy.

Protein Structure

TLR2 consists of approximately 784 amino acids and is a type I transmembrane protein with distinct structural domains critical for its function:

Extracellular Domain:

• The extracellular domain is the largest region, spanning about 500-600 amino acids and composed primarily of leucine-rich repeats (LRRs). These LRRs form a horseshoe-shaped solenoid structure that enables ligand recognition. TLR2’s ligand specificity stems from these LRR motifs, which bind directly to microbial components.
• TLR2 is unique in its ability to form heterodimers with TLR1 and TLR6, increasing its repertoire of ligands. The LRR region is essential for this dimerization, allowing TLR2 to engage with triacylated and diacylated lipopeptides from bacterial cell walls, which are structurally specific to Gram-negative and Gram-positive bacteria, respectively.
• N-glycosylation sites within the LRR domain contribute to the protein’s stability and proper folding, ensuring it reaches the cell surface effectively.

Transmembrane Domain:

• TLR2 possesses a single transmembrane helix of about 20-25 amino acids, which anchors it within the cell membrane. This domain stabilizes TLR2’s position and plays a role in its dimerization with TLR1 or TLR6. It also facilitates efficient ligand recognition and receptor activation through conformational changes upon ligand binding.

Intracellular Domain (TIR Domain):

• The intracellular region contains the Toll/Interleukin-1 receptor (TIR) domain, approximately 150 amino acids in length, which is essential for downstream signaling. The TIR domain mediates interactions with adaptor proteins, such as MyD88 (myeloid differentiation primary response 88), that propagate signaling to downstream effectors.
• This domain contains conserved motifs necessary for binding other TIR-containing proteins. The structure of the TIR domain facilitates interactions with signaling adaptors, leading to activation of immune responses, particularly by inducing NF-κB and MAPK pathways.

Classification and Subtypes

TLR2 is classified as a member of the TLR family and is grouped with TLR1 and TLR6 in a subfamily based on structural similarities and dimerization capabilities. TLR2’s ability to form heterodimers with TLR1 and TLR6 allows it to detect a broader range of microbial components:

• TLR1/TLR2 heterodimer: Recognizes triacylated lipoproteins, primarily from Gram-negative bacteria. This dimerization extends TLR2’s recognition capability.
• TLR2/TLR6 heterodimer: Recognizes diacylated lipoproteins, commonly found in Gram-positive bacteria. This specificity enables immune responses against diverse bacterial pathogens.
• TLR2/TLR10 interactions (less characterized): While TLR10’s exact function remains unclear, evidence suggests it may modulate TLR2 signaling or contribute to immune response regulation.

This versatility allows TLR2 to act as a broad-spectrum sensor within the immune system, recognizing a wide array of microbial components.

Function and Biological Significance

TLR2 has several key functions related to pathogen recognition and immune activation:

Ligand Recognition and Dimerization:

• The TLR2/TLR1 and TLR2/TLR6 heterodimers enable recognition of microbial lipoproteins. TLR2’s extracellular LRR domains bind directly to pathogen components, leading to receptor activation.
• Through dimerization, TLR2 is versatile in recognizing both Gram-positive and Gram-negative bacteria as well as fungal pathogens. This broad specificity allows TLR2 to be a front-line receptor in the innate immune response.

Signal Transduction:

• Once activated, TLR2 initiates signaling by recruiting adaptor proteins such as MyD88 and TIRAP (TIR domain-containing adapter protein). These adaptors engage downstream molecules, leading to activation of the NF-κB and MAPK pathways.
• The activation of NF-κB results in the transcription of pro-inflammatory cytokines, including TNF-α, IL-6, and IL-1β, which mediate inflammatory responses and recruit other immune cells to the infection site.
• The MAPK pathway further enhances immune responses, contributing to the activation and differentiation of immune cells, which enhances the body’s capacity to neutralize invading pathogens.

Role in Host Defense and Inflammation:

• TLR2 plays a critical role in detecting bacterial infections, especially in infections caused by pathogens such as Staphylococcus aureus, Mycobacterium tuberculosis, and Candida albicans.
• Its role extends to recognizing viral components, where it may participate in immune responses against viral pathogens like herpes simplex virus (HSV) and respiratory syncytial virus (RSV).
• TLR2 activation is essential for initiating inflammation, which, while beneficial in infections, can also contribute to chronic inflammatory states if dysregulated.

Influence on Adaptive Immunity:

• TLR2 signaling helps bridge innate and adaptive immunity by enhancing antigen presentation and cytokine production, which in turn promotes T-cell activation.
• This function is significant for developing long-term immune memory, thus influencing the body’s ability to respond to pathogens upon re-exposure.

Clinical Issues

Aberrations in TLR2 function or expression have been associated with various infectious, autoimmune, and inflammatory diseases:

Infectious Diseases:

• TLR2 polymorphisms have been linked to differential susceptibility to infections such as tuberculosis and leprosy. Variants in TLR2 can alter ligand binding and signaling efficacy, impacting immune response strength.
• TLR2’s broad ligand recognition spectrum is critical for its role in defense against bacterial and fungal pathogens, making it a key factor in immune responses to infections caused by Gram-positive bacteria like Streptococcus pneumoniae and Staphylococcus aureus.

Autoimmune and Inflammatory Diseases:

• Dysregulated TLR2 activation is implicated in autoimmune disorders, including rheumatoid arthritis and systemic lupus erythematosus (SLE). Excessive TLR2 activity leads to persistent inflammation, contributing to tissue damage and autoimmune progression.
• Chronic activation of TLR2 by endogenous ligands, such as heat shock proteins or high-mobility group box proteins, can sustain inflammation in diseases like atherosclerosis and multiple sclerosis.

Cancer:

• The role of TLR2 in cancer is complex; it can either promote anti-tumor immunity or foster a tumor-supportive microenvironment depending on context.
• Persistent TLR2 activation in the tumor microenvironment may promote chronic inflammation, which can facilitate tumor growth and metastasis. Conversely, TLR2 agonists are also being investigated as immunotherapy adjuvants to enhance anti-tumor immune responses.

Therapeutic Targeting:

• TLR2 has become a therapeutic target for modulating immune responses. TLR2 agonists are explored as vaccine adjuvants to enhance immune response strength, while TLR2 antagonists are considered for treating inflammatory conditions by reducing excessive inflammation.
• Therapeutic strategies aim to harness TLR2’s signaling to improve responses in infectious diseases, vaccines, and autoimmune conditions, making it a promising area for immune modulation research.

Summary

TLR2 is a vital component of the innate immune system, enabling the detection of bacterial, fungal, and viral components. Through its extracellular leucine-rich repeat domains, TLR2 binds pathogen-associated molecules and, through dimerization with TLR1 or TLR6, broadens its ligand specificity. This dimerization and subsequent activation of downstream signaling pathways, including NF-κB and MAPK, initiate pro-inflammatory cytokine production and immune cell recruitment.

TLR2’s clinical relevance is evident in infectious diseases, autoimmune disorders, chronic inflammation, and cancer. Genetic variations in TLR2 can affect susceptibility to infections and inflammatory diseases, while chronic TLR2 activation can drive pathological inflammation. As a result, TLR2 is a target for therapeutic interventions aimed at modulating immune responses. By fine-tuning TLR2 activity, researchers aim to optimize immune responses in infections and inflammatory diseases and explore its potential in vaccine and cancer therapies.