Toll-Like Receptor 2
Toll-like receptors (TLRs) are expressed in immune cells such as dendritic cells and macrophages and recognize pathogens (Takeda and Akira 2005). Along with four other TLRs, human TLR2 was first named and reported as a receptor similar to the Drosophila Toll protein in 1998 (Rock et al. 1998). TLR2 gene, with a size of 21,836 bases on chromosome 4, encodes the TLR2 protein. TLR2 is one of the pattern recognition receptors (PRRs) that sense pathogen-associated molecular patterns (PAMPs) of microbes and thus act as a first line of host defense (Janeway and Medzhitov 2002). The triggering of an innate immune response by PRRs after recognition of conserved microbial components and further development of the adaptive immunity were first described by Charles A. Janeway Jr. (Janeway 1989). The initial understanding of the TLR2 ligand was obtained in 1999 when a study revealed that TLR2 recognizes components of gram-positive bacteria, in contrast to TLR4, which binds to lipopolysaccharides of gram-negative bacteria (Takeuchi et al. 1999). A study first showed that danger-associated molecular patterns (DAMPs) also bind to TLRs and trigger inflammatory responses (Medzhitov and Janeway 2002). The dimerization mechanism of TLR2 with TLR1 or TLR6 for recognition of ligands and induction of cytokine production was first described in 2000 (Ozinsky et al. 2000). TLR2 participates in the myeloid differentiation primary-response protein 88 (MyD88)-dependent signaling pathway that is well known after several years of research aimed at identification of the currently known signaling molecules. The association of TLR2 with diseases was first reported in 2000, when the Bacillus Calmette–Guérin vaccine for tuberculosis was found to cause dendritic-cell maturation through TLR2 and TLR4 signaling (Tsuji et al. 2000).
Structure of TLR2
Ligand Recognition by TLR2
TLRs from vertebrates can be subdivided into six subfamilies based on evolution and the type of ligands they recognize. They are TLR1/2/6/10, 3, 4, 5, TLR7/8/9, and TLR11/12/13/21/22/23 (Roach et al. 2005). The members that are expressed on the cell surface are TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11. TLR2 mainly recognizes lipopeptides that are mostly expressed on the external membrane of gram-positive bacteria. TLR2 binds to a wide variety of ligands from several species of pathogens to initiate TLR2 signaling that induces cytokines (Oliveira-Nascimento et al. 2012). The ECD of TLR2 can sense ligands from several microbes, and they include lipopeptides, lipoteichoic acid (LTA), glycosylphosphatidylinositols (GPIs), and phospholipomannan. DAMPs released by dying cells or during a disease can activate TLRs, and these receptors may play a protective role or cause immune disorders. To bind to the cognate ligand, TLR dimers bind to cofactors that help to deliver the appropriate ligand to TLRs. TLR2 in association with coreceptors such as cluster of differentiation (CD) 36 and CD14 recognize a few ligands but not all (Lee et al. 2012). The innate immune responses to the TLR2 ligands LTA and R-macrophage-activating lipopeptide 2 (MALP2) are improved by CD36. Tumor necrosis factor (TNF)-α production triggered by several TLR2 binders is associated with CD14. Other accessory molecules that facilitate TLR2 ligand detection include guanyl nucleotide−releasing protein 94, integrin, dectin-1, and chemokine receptor type 4 (Lee et al. 2012). DAMPs are also recognized by TLR2, in particular, versican, high-mobility group box (HMGB) 1, pancreatic adenocarcinoma upregulated factor, amyloid β, α-synuclein, serum amyloid A, synaptosome-associated protein, and β2-glycoprotein I (van Bergenhenegouwen et al. 2013). The recognition of Pam3CSK4 by human TLR2-TLR1 has been analyzed by X-ray crystallography, and these data provide a detailed picture of atomic interactions between human TLR2 and its ligand (Fig. 2b and c). In addition, Pam2CSK4 with two acyl chains induces heterodimerization of mouse TLR2 with mouse TLR6; this process was also analyzed by X-ray crystallography. For TLR2, both available crystal structures with agonists show conserved interactions of TLR2 with Asp327 and Phe349, but these interactions are absent in the complex of TLR2 with Streptococcus pneumoniae LTA (pnLTA) or with phosphatidylethanolamine-diethylene triamine penta-acetic acid (PE-DTPA); these complexes fail to activate TLR2 signaling because of the special binding mode (Kang et al. 2009). After these two diacyl lipopeptide ligands bind to the TLR2 monomer, oxygen atoms in the head group of the ligand repel the hydrophobic sulfur site in TLR2, shifting the head group to a position that differs from that observed in lipopeptides (Kang et al. 2009). This head group rotation disrupts hydrogen bonding between the peptide head group, Asp327 and Phe349, thus inhibiting heterodimerization of TLR2 with TLR1 or TLR6, which is essential for activation of TLR2 signaling.
MyD88-Dependent TLR2 Signaling
The Role of TLR2 in Diseases
Genetic variations in humans have clarified the role of TLRs in infectious and autoimmune diseases. The outcomes due to single nucleotide polymorphisms in genes encoding TLR2 and the molecules that are essential for TLR2 signaling are known to cause serious diseases and some are discussed below. The G2258A polymorphism in TLR2 reduces the ligand-induced TLR2 activation and increases the risk of asymptomatic bacteriuria in females (Medvedev 2013). The R753Q polymorphism in TLR2 poses a risk of sepsis, atopic dermatitis, and tuberculosis (Medvedev 2013). Deletion of nucleotides between positions −196 and −174 in the promoter region of the TLR2 gene may be involved in carcinogenesis and can increase the risk of prostate and cervical cancer among North Indians (Medvedev 2013). A rare TLR2 polymorphism, P631H, is believed to be associated with systemic sclerosis, tuberculosis, and progression of pulmonary arterial hypertension (Medvedev 2013). Patients infected with Trypanosoma cruzi who have the S180L polymorphism in MAL show poor ligand-induced TLR2 signaling, which inhibits the progression of Chagas disease (Ramasawmy et al. 2009). Apolipoprotein-CIII activates monocytes via TLR2 and contributes to atherosclerosis, whereas TLR2 knockout mice show reduced atherosclerosis; one or more TLR2 DAMP agonists that are released in cells other than bone marrow cells are known to cause TLR2-promoted atherosclerosis (Yamashita et al. 2006). TLR2 expression is stronger in various cells of patients with rheumatoid arthritis (RA), and rodents treated with the streptococcal cell wall develop joint swelling that is TLR2 dependent. HMGB1, a TLR2 DAMP, is involved in the pathogenesis of RA (Keogh and Parker 2011). Serum amyloid A, another TLR2 DAMP that is expressed more actively in RA patients, may also be involved in the initiation or progression of RA (Keogh and Parker 2011). TLR2 expression in monocytes is increased in patients with autoimmune diabetes; this observation indicates that TLR2 may initiate this disease by recognizing β-cell death (Keogh and Parker 2011). OPN-305 is an antiTLR2 antibody that was found to be effective against ischemia-reperfusion injury in pigs (Arslan et al. 2012). T2.5 (an antiTLR2 antibody) prevents sepsis in mice during coadministration with 1A6 (an antiTLR4 antibody) (Lima et al. 2015).
TLR2 has been implicated in several infectious diseases and autoimmune disorders, and hence targeting of TLR2 through modulators to either activate or inhibit its activity can have therapeutic benefits. Accumulating evidence on TLR2 expression and TLR2-induced cytokine production during some diseases proves the role of TLR2 in initiation or progression (or both) in these pathologies. Targeting TLR2 alone should be more beneficial than targeting the molecules involved in TLR2 signaling because the latter approach may lead to needless inhibition of cytokines induced by other TLRs. Several diseases involve both TLR2 and TLR4; thus, the understanding of the molecular mechanisms underlying the pathological role of TLR2 and other TLRs in a particular disease will help to design inhibitors or activators accordingly. The knowledge about all the TLRs involved in a particular innate immune disorder can help to identify a single inhibitor that targets multiple TLRs. Rather than developing synthetic high-molecular-weight compounds targeting TLR2, it is more rational to design drug-like and peptidomimetic compounds that have suitable pharmacokinetic and pharmacodynamic properties. Similarly, screening of natural compounds to identify TLR2 modulators is also effective. Molecules that modulate TLR2 signaling or exert their effects through direct binding to TLR2 are scarce. Hence, more studies on the structure–activity relation are needed to modify and increase the efficiency of the existing TLR2 modulators in addition to the effort to discover molecules with different chemical structures.
This work was supported by the National Research Foundation of Korea (NRF-2015R1A2A2A09001059).
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