Alternative titles; symbols
HGNC Approved Gene Symbol: TLR2
Cytogenetic location: 4q31.3 Genomic coordinates (GRCh38): 4:153,684,280-153,710,637 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 4q31.3 | {Colorectal cancer, susceptibility to} | 114500 | Autosomal dominant; Somatic mutation | 3 |
| {Leprosy, susceptibility to} | 246300 | Autosomal dominant | 3 | |
| {Mycobacterium tuberculosis, susceptibility to} | 607948 | 3 |
In Drosophila, the Toll transmembrane receptor plays a central role in the signaling pathways that control dorsal-ventral axis formation and the innate nonspecific immune response. This Toll-mediated immune response reflects an ancestral conserved signaling system that has homologous components in a wide range of organisms. By searching an EST database for human Toll homologs, Chaudhary et al. (1998) identified cDNA sequences from 2 genes that they called TIL3 (TLR5; 603031) and TIL4. Both TIL3 and the predicted 784-amino acid TIL4 protein contain the characteristic Toll motifs: an extracellular leucine-rich repeat (LRR) domain and a cytoplasmic interleukin-1 receptor (IL1R; 147810)-like region. Northern blot analysis revealed that TIL4 is expressed as a 2.8-kb transcript that is most abundant in peripheral blood leukocytes. Chaudhary et al. (1998) found that, like IL1R and TLR4 (603030), TIL3 and TIL4 were able to activate NF-kappa-B (see 164011), though in a cell-type-specific fashion. The authors concluded that TLR4, TIL3, and TIL4 are a family of genes with conserved structural and functional features involved in immune modulation. Independently, Rock et al. (1998) identified cDNAs from TIL4, or TLR2, and 4 other Toll-like receptor (TLR) genes. By use of Northern blots, Rock et al. (1998) found that TLR2 is expressed as 4- and 4.4-kb mRNAs in heart, brain, and muscle.
The generation of cell-mediated immunity against many infectious pathogens involves the production of interleukin-12 (see IL12B; 161561), a key signal of the innate immune system. Yet, for many pathogens, the molecules that induce interleukin-12 production by macrophages and the mechanisms by which they do so remain undefined. Brightbill et al. (1999) demonstrated that microbial lipoproteins are potent stimulators of interleukin-12 production by human macrophages and that induction is mediated by TLRs. Several lipoproteins stimulated TLR-dependent transcription of inducible nitric oxide synthase (iNOS; 163730) and the production of nitric oxide, (NO) a powerful microbicidal pathway. Activation of TLRs by microbial lipoproteins may initiate innate defense mechanisms against infectious pathogens.
Aliprantis et al. (1999) found that bacterial lipoproteins induced apoptosis in THP-1 monocytic cells through human TLR2. In addition, bacterial lipoproteins also initiated apoptosis in an epithelial cell line transfected with TLR2. Bacterial lipoproteins stimulated NF-kappa-B, a transcriptional activator of multiple host defense genes, and activated the respiratory burst through TLR2. Thus, Aliprantis et al. (1999) concluded that TLR2 is a molecular link between microbial products, apoptosis, and host defense mechanisms.
Aderem and Ulevitch (2000) reviewed the role of TLRs in innate immunity. Whereas lipopolysaccharide (LPS) activates cells through TLR4, gram-positive cell-wall components, including peptidoglycan and lipoteichoic acid, as well as mycobacterial cell-wall components such as lipoarabinomannan and mycolylarabinogalactan, and yeast cell-wall zymosan, activate cells via TLR2. In an in vitro system with mouse macrophages, Underhill et al. (1999) showed that TLR2 discriminates between pathogen types inside phagosomes.
Using Northern blot analysis, Muzio et al. (2000) determined the differential expression pattern of the TLRs in leukocytes. TLR2, like TLR4 and TLR5, was expressed in myelomonocytic cells. In contrast with TLR4, exposure to lipopolysaccharide upregulated TLR2 only in granulocytes and not in monocytes, and its expression was unaffected by IL10 (124092).
Using RT-PCR and ELISA analysis, Kadowaki et al. (2001) defined the differential expression of TLR1 through TLR10 and the pathogen-associated molecular pattern recognition profiles and cytokine production patterns of monocytes and dendritic cell precursors. They concluded that neither monocytes nor dendritic cell precursors can respond to all microbial antigens and that they have limited functional plasticity.
Using agonists specific for TLR4 (LPS) and TLR2 (peptidoglycan of S. aureus), Re and Strominger (2001) showed differential cytokine expression patterns in dendritic cells (DCs) by RNase protection and ELISA analysis. Stimulation of TLR4 but not of TLR2 promoted expression of the Th1-inducing cytokine IL12 p70 heterodimer and the gamma-interferon (IFNG; 147570) inducible chemokine protein IP10 (CXCL10; 147310). TLR2 stimulation resulted in the release of the IL12 inhibitory p40 homodimer, which favors Th2 development, and the chemokines IL8 (146930) and IL23/p19 (IL23A; 605580). Re and Strominger (2001) suggested that the failure of TLR2-stimulated DCs to produce CXCL10 may result in defective recruitment of Th1 cells that preferentially express the CXCL10 receptor, CXCR3 (300574). They concluded that TLRs can translate the information regarding the nature of pathogens into differences in the cytokines and chemokines produced by DCs, which will in turn differentially polarize adaptive immune responses.
Harju et al. (2001) found that expression of Tlr2 and Tlr4 increased in fetal mouse lung with age. Expression increased sharply after birth and into adulthood. In contrast, no developmental trends were detectable in liver. In placenta, expression of Tlr4 decreased during the second half of pregnancy, while Tlr2 expression was constant and significantly lower throughout gestation.
Using the 19-kD lipoprotein of Mycobacterium tuberculosis to activate mouse and human macrophages, Thoma-Uszynski et al. (2001) determined that the viability of intracellular M. tuberculosis bacteria was significantly reduced in macrophages of both species expressing TLR2. Macrophages from Tlr2-deficient mice or human macrophages blocked by anti-TLR2 antibodies failed to kill the bacteria. In mice, the reduction of M. tuberculosis viability was found to be mediated by the induction of iNOS and the release of NO, which were undetectable in human monocytes and alveolar macrophages. Stimulation of iNOS and NO is also mediated by IFNG and tumor necrosis factor (TNF; 191160) in mice. However, IFNG and TNF failed to induce NO or exert any antimicrobial effect in human macrophages. Thoma-Uszynski et al. (2001) proposed that TLR2-induced activation of human monocyte/macrophage cells may lead to the production of antimicrobial peptides similar to the metchnikowan, defensin (see 600471), cecropin, and drosomycin peptides induced in Drosophila.
Hirschfeld et al. (1999) showed that expression of TLR2, facilitated by CD14 (158120), confers responsiveness, as measured by cytokine production, to a number of B. burgdorferi antigens, including lipoproteins and lipopeptides, but relatively little responsiveness to LPS. The authors concluded that TLR2 facilitates the inflammatory events associated with Lyme arthritis.
Alexopoulou et al. (2002) reported that a small percentage of individuals who receive a vaccination series with the OspA antigen of B. burgdorferi, the causative spirochete agent of Lyme disease, have very low antibody responses to the vaccine. They studied 7 of these 'low responders.' Macrophages from the low responders produced lower levels of the proinflammatory cytokines TNF and interleukin-6 (IL6; 147620), while production of the antiinflammatory cytokine IL10 was similar to that of normal responders. Mutation analysis did not identify any defects in the TLR2 gene in the low responders. However, Tlr2-deficient mice produced lower levels of antibody and IL6 in response to OspA in the absence of complete Freund adjuvant (CFA), but not to intact B. burgdorferi. Apart from a higher spirochete burden early in the course of the disease, Tlr2 -/- mice resolved the infection in a manner similar to wildtype mice. Tlr1 (601194)-deficient mice had a similar pattern of responses, except that these mice were capable of producing IL6 in response to peptidoglycan and were also capable of making IL10 in response to OspA. The human low antibody responders had no mutations in the TLR1 gene. However, flow cytometric analysis demonstrated undetectable cell-surface expression of TLR1, but not of TLR2, in all but 1 of the low responders. Alexopoulou et al. (2002) concluded that although TLR1 expression is critical for antibody responses to OspA, the presence of other TLRs in the host that presumably recognize other B. burgdorferi antigens results in no greater susceptibility to infection and disease in these hosts.
Using homologous recombination, Takeuchi et al. (2002) generated mice deficient in Tlr1, but not Tlr2. Macrophages from Tlr1-deficient mice stimulated with mycobacteria or with a mycobacterial 19-kD lipoprotein had impaired production of TNFA and IL6. Responses to mycoplasmal diacylated lipoproteins, but not to bacterial triacylated lipoproteins, was normal in Tlr1-deficient macrophages. Immunoprecipitation analysis indicated that TLR1 and TLR2 associated in a ligand-independent manner in human embryonic kidney cells. Takeuchi et al. (2002) concluded that TLR1 is involved in the recognition of triacylated lipoproteins and mycobacterial products, and that TLR2 pairs with TLR1 or TLR6 (605403) to recognize different pathogen-associated molecular patterns, or PAMPs.
Krutzik et al. (2003) showed that TLR2-TLR1 heterodimers mediated the strongest cell activation by killed Mycobacterium leprae. Human cell lines transiently expressing homodimers of any of the 10 TLRs except TLR2 did not mediate responsiveness. A genomewide scan of M. leprae detected 31 putative lipoproteins. Synthetic lipopeptides representing the 19- and 33-kD lipoproteins activated both monocytes and dendritic cells, as measured by IL12B release. This activation and TLR1 expression could be enhanced by type-1 cytokines, such as IFNG or GMCSF (CSF2; 138960), whereas type-2 cytokines, such as IL4 (147780), inhibited activation and downregulated TLR2 expression on both monocytes and dendritic cells. Both TLR2 and TLR1 were more strongly expressed in lesions from patients with the resistant tuberculoid form of the disease (see 246300), which is associated with type-1 cytokine expression and low numbers of mycobacteria. In contrast, in lesions from patients with the lepromatous form, which is characterized by disseminated leprosy bacilli and weak specific cell-mediated immunity with type-2 cytokines, there was reduced TLR2 and TLR1 expression. However, peripheral blood monocytes and dendritic cells from both patient groups were responsive to the 19-kD lipoprotein in the presence or absence of IFNG. Krutzik et al. (2003) concluded that local expression and activation of TLRs contribute to the host response against pathogens, but they may also be implicated in inflammation-induced nerve injury in tuberculoid leprosy.
Damage to peripheral sensory nerves is a major cause of morbidity in leprosy patients. The Schwann cell is the principal host of Mycobacterium leprae, and colonization of Schwann cells stimulates granuloma formation and cell-mediated nerve injury. Oliveira et al. (2003) noted that whole M. leprae favors Schwann cell survival rather than apoptosis. In contrast, they found that activation of a human Schwann cell line and primary human Schwann cell cultures with a TLR2 agonist, a synthetic lipopeptide comprising the N-terminal portion of the M. leprae 19-kD lipoprotein, triggered an increase in the number of apoptotic cells. The lipopeptide-induced apoptosis could be blocked by anti-TLR2 antibody. Schwann cells in lesions from leprosy patients expressed TLR2, and some of the cells had undergone apoptosis. Oliveira et al. (2003) proposed that breakdown of M. leprae either before or during treatment may release bacterial molecules capable of activating TLRs, inducing Schwann cell apoptosis.
Sato et al. (2006) found that some laboratory strains and clinical isolates of herpes simplex viruses triggered surface-expressed TLR2 and induced IL6 and IL12 in classical dendritic cells, and some of these strains also activated intracellular TLR9 (605474). Plasmacytoid dendritic cells recognized all strains through TLR9. Sato et al. (2006) proposed that cells expressing multiple TLRs can detect pathogens with multiple molecular patterns in an orchestrated manner, linking uptake and degradation of pathogens to microbial recognition.
Using PCR, Western blot, and immunohistochemical analyses, Schauber et al. (2007) found that human skin wounding led to upregulation of TLR2, the TLR coreceptor CD14 (158120), and the vitamin D3 catabolic enzyme CYP24A1 (126065). TLR2 protein expression was detectable on keratinocytes at the wound edges. Active vitamin D3 (1,25D3) enhanced TLR2 and CD14 expression in cultured keratinocytes. CYP27B1 (609506) expression increased in response to injury, TGFB1 (190180) treatment, or TLR2 activation and resulted in a corresponding increase in expression of 1,25D3-responsive genes in a CYP27B1-dependent manner. Keratinocytes stimulated with 1,25D3 displayed enhanced TLR2 function and cathelicidin expression. Schauber et al. (2007) concluded that vitamin D3 is important in innate immunity, enabling keratinocytes to recognize and respond to microbes to protect wounds against infection.
To understand how cancer cells infect the inflammatory microenvironment, Kim et al. (2009) conducted a biochemical screen for macrophage-activating factors secreted by metastatic carcinomas. They demonstrated that, among the cell lines screened, Lewis lung carcinoma (LLC) were the most potent macrophage activators leading to production of interleukin-6 (IL6; 147620) and tumor necrosis factor-alpha (191160) through activation of the Toll-like receptor family members TLR2 and TLR6 (605403). Both TNF-alpha and TLR2 were found to be required for LLC metastasis. Biochemical purification of LLC-conditioned medium led to identification of the extracellular matrix proteoglycan versican (118661), which is upregulated in many human tumors including lung cancer, as a macrophage-activator that acts through TLR2 and its coreceptors TLR6 and CD14. By activating TLR2:TLR6 complexes and inducing TNF-alpha secretion by myeloid cells, versican strongly enhances LLC metastatic growth. Kim et al. (2009) concluded that their results explained how advanced cancer cells usurp components of the host innate immune system, including bone marrow-derived myeloid progenitors, to generate an inflammatory microenvironment hospitable for metastatic growth.
Using flow cytometry, fluorescence microscopy, and RT-PCR analysis of mouse splenic dendritic cells from wildtype or Tlr2 -/- mice, Manicassamy et al. (2009) showed that Tlr2 and dectin-1 (CLEC7A; 606264) both recognized the microbial stimulus zymosan, but they stimulated distinct innate and adaptive responses. Tlr2 signaling induced expression of Raldh2 (ALDH1A2; 603687) and Il10 to metabolize vitamin A and stimulate Foxp3 (300292)-positive T-regulatory (Treg) cells. Raldh2 converted vitamin A-derived retinal to retinoic acid, which acted in an autocrine manner to induce expression of Socs3 (604176) and suppress activation of p38 (MAPK14; 600289) and proinflammatory cytokines. The Treg cells suppressed the Th1 and Th17 (see IL17A; 603149) responses that mediate autoimmunity in mice. In mice lacking Tlr2, dectin-1-mediated signaling induced Il23 and potent Th1 and Th17 responses, accompanied by exacerbated autoimmunity. Manicassamy et al. (2009) proposed that these data demonstrate a mechanism for systemic induction of retinoic acid and immune suppression against autoimmunity.
Alves-Filho et al. (2009) reported that Cxcr2 (IL8RB; 146928) was dramatically downregulated in neutrophils of wildtype mice with severe sepsis, which correlated with reduced chemotaxis to Cxcl2 in vitro. Mice lacking Tlr2 did not downregulate Cxcr2 and exhibited higher bacterial clearance, lower serum inflammatory cytokines, and improved survival during severe sepsis. In vitro experiments showed that the Tlr2 agonist lipoteichoic acid (LTA) downregulated Cxcr2 expression and markedly inhibited neutrophil chemotaxis and actin polymerization induced by Cxcl2. Activation of wildtype neutrophils, but not Tlr2 -/- neutrophils, with LTA resulted in enhanced expression of Grk2 (ADRBK1; 109635). Activated neutrophils adoptively transferred to wildtype mice were less able to migrate to inflammatory sites. Alves-Filho et al. (2009) concluded that defective neutrophil migration during polymicrobial sepsis may be linked to a detrimental role of TLR2.
Tanigawa et al. (2009) found that CORO1A (605000) suppressed TLR signaling following expression in a human monocytic cell line. TLR2-mediated activation of the innate immune response resulted in suppression of CORO1A expression. However, in cells infected with M. leprae, TLR2-mediated CORO1A suppression was inhibited, as was NFKB activation. Tanigawa et al. (2009) proposed that the balance between TLR2-mediated signaling and CORO1A expression is key in determining the fate of M. leprae after infection.
Almeida et al. (2009) used Mycobacterium bovis BCG as a model organism to study the formation of lipid droplets in macrophages during infection. They found that BCG infection increased expression of Pparg (601487) in mouse peritoneal macrophages. Lipid body formation was reduced in macrophages lacking Tlr2 and increased following treatment with a Pparg agonist. Treatment with a Pparg antagonist reduced lipid body formation without inhibiting cytokine production and enhanced mycobactericidal activity of macrophages. Almeida et al. (2009) concluded that PPARG is involved in lipid body biogenesis, which is linked to TLR2 and to mycobacterial pathogenesis.
West et al. (2010) demonstrated that the end products of lipid oxidation, omega-(2-carboxyethyl) pyrrole (CEP) and other related pyrroles, are generated during inflammation and wound healing and accumulate at high levels in aging tissues in mice and in highly vascularized tumors in both murine and human melanoma. The molecular patterns of carboxyalkylpyrroles are recognized by TLR2, but not by TLR4 (603030) or scavenger receptors on endothelial cells, leading to an angiogenic response that is independent of VEGF (192240). CEP promoted angiogenesis in hindlimb ischemia and wound healing models through MyD88 (602170)-dependent TLR2 signaling. Neutralization of endogenous carboxyalkylpyrroles impaired wound healing and tissue revascularization and diminished tumor angiogenesis. Both TLR2 and MyD88 are required for CEP-induced stimulation of RAC1 (602048) and endothelial migration. West et al. (2010) concluded that, taken together, their findings established a new function for TLR2 as a sensor of oxidation-associated molecular patterns, providing a key link connecting inflammation, oxidative stress, innate immunity, and angiogenesis.
Round et al. (2011) demonstrated that the prominent gut commensal Bacteroides fragilis activates the TLR pathway to establish host-microbial symbiosis. TLR2 on CD4+ T cells is required for B. fragilis colonization of a unique mucosal niche in mice during homeostasis. A symbiosis factor (PSA, polysaccharide A) of B. fragilis signals through TLR2 directly on Foxp3+ regulatory T cells to promote immunologic tolerance. B. fragilis lacking PSA is unable to restrain T helper 17 (Th17; see 603149) cell responses and is defective in niche-specific mucosal colonization. Therefore, Round et al. (2011) concluded that commensal bacteria exploit the TLR pathway to actively suppress immunity, and proposed that the immune system can discriminate between pathogens and the microbiota through recognition of symbiotic bacterial molecules in a process that engenders commensal colonization.
West et al. (2011) demonstrated that engagement of a subset of Toll-like receptors (TLR1, 601194; TLR2; and TLR4, 603030) results in the recruitment of mitochondria to macrophage phagosomes and augments mitochondrial reactive oxygen species (mROS) production. This response involves translocation of a TLR signaling adaptor, TRAF6 (602355), to mitochondria, where it engages the protein ECSIT (608388), which is implicated in mitochondrial respiratory chain assembly. Interaction with TRAF6 leads to ECSIT ubiquitination and enrichment at the mitochondrial periphery, resulting in increased mitochondrial and cellular ROS generation. ECSIT- and TRAF6-depleted macrophages have decreased levels of TLR-induced ROS and are significantly impaired in their ability to kill intracellular bacteria. Additionally, reducing macrophage mROS levels by expressing catalase (115500) in mitochondria results in defective bacterial killing, confirming the role of mROS in bactericidal activity. West et al. (2011) concluded that their results revealed a novel pathway linking innate immune signaling to mitochondria, implicated mROS as an important component of antibacterial responses, and further established mitochondria as hubs for innate immune signaling.
Using proteomic analysis, Toubiana et al. (2011) found that stimulation of a human monocyte cell line with TLR2 agonists resulted in rapidly increased expression of posttranslationally modified IMPDHII (IMPDH2; 146691) in lipid rafts. Mass spectrometric and immunoprecipitation analyses determined that the IMPDHII modification involved tyrosine phosphorylation. Luciferase analysis showed that IMPDHII inhibited NFKB activity and reduced TNF production, but IMPDHII did not modify MAP kinase activation or prevent degradation of IKB (see 164008). IMPDHII inhibited phosphorylation of p65 (RELA; 164014) and modulated PI3K (see 601232) activation upstream of AKT (164730). IMPDHII inhibition of NFKB activation involved dephosphorylation of the p85-alpha subunit (PIK3R1; 171833) of PI3K through increased SHP1 (PTPN6; 176883) activity. Toubiana et al. (2011) concluded that IMPDHII has a negative role in TLR2 signaling.
Shirey et al. (2013) reported that CD14 (158120) and TLR2 are required for protection against influenza-induced lethality in mice mediated by Eritoran (also known as E5564), a potent, well-tolerated, synthetic TLR4 antagonist. Therapeutic administration of Eritoran blocked influenza-induced lethality in mice, as well as lung pathology, clinical symptoms, cytokine and oxidized phospholipid expression, and decreased viral titers. CD14 directly binds Eritoran and inhibits ligand binding to MD2 (605243). Shirey et al. (2013) concluded that Eritoran blockade of TLR signaling represents a novel therapeutic approach for inflammation associated with influenza, and possibly other infections.
Zhang et al. (2015) used in vivo aging analyses in mice to demonstrate that neutrophil proinflammatory activity correlates positively with their aging while in circulation. The authors found that aged neutrophils represent an overly active subset exhibiting enhanced alpha-M (120980)-beta-2 (600065) integrin activation and neutrophil extracellular trap formation under inflammatory conditions. Zhang et al. (2015) showed that neutrophil aging is driven by the microbiota via Toll-like receptor (TLR4, 603030 and TLR2)- and myeloid differentiation factor-88 (MYD88; 602170)-mediated signaling pathways. Depletion of the microbiota significantly reduced the number of circulating aged neutrophils and dramatically improved the pathogenesis and inflammation-related organ damage in models of sickle cell disease (603903) or endotoxin-induced septic shock. Zhang et al. (2015) concluded that their results identified a role for the microbiota in regulating a disease-promoting neutrophil subset.
TLRs and IL1Rs share a conserved cytoplasmic TIR domain. Mutations in this domain disrupt responses to LPS and to gram-positive bacteria, mediated by TLR4 and TLR2, respectively. By structural analysis, Xu et al. (2000) determined that the TIR domains of human TLR2 and TLR1, which are 50% identical at the amino acid level, contain a central 5-stranded parallel beta-sheet surrounded by 5 alpha helices on both sides. The structures have a large conserved surface patch, and mutational and functional analyses indicated that residues in the surface patch are crucial for receptor signaling. The authors concluded that instead of disturbing the structure of the TIR domain, mutations may abolish signaling by disrupting the recruitment of the MYD88 (602170) adaptor molecule.
Chaudhary et al. (1998) mapped the TLR2 gene to 4q31.3-q32 by fluorescence in situ hybridization. Using the same technique, Rock et al. (1998) refined the map location to 4q32.
Susceptibility to Leprosy 5
Kang and Chae (2001) identified an arg677-to-trp polymorphism (R677W; 603028.0001) in the intracellular domain of TLR2 in 10 (22%) of 45 Korean lepromatous leprosy (246300) patients, but not in any of 41 Korean tuberculoid patients or 45 Korean controls. Bochud et al. (2003) found that wildtype TLR2 mediated CD14-enhanced Mycobacterium leprae-dependent activation of NFKB, but TLR2 containing R677W did not. They concluded that TLR2 is necessary to mediate responsiveness to M. leprae and that the impaired function of the R677W variant provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy.
Malhotra et al. (2005) used a case control study to investigate whether the R677W SNP in TLR2 reported by Kang and Chae (2001) was associated with leprosy susceptibility in 286 Indian leprosy patients and 183 ethnically matched controls. Genotyping results after direct PCR sequencing led Malhotra et al. (2005) to conclude that the R677W polymorphism is not a true polymorphism of TLR2, but rather resulted from variation present in a duplicated region 23 kb upstream of TLR2 that shares 93% identity with TLR2 exon 3. Malhotra et al. (2005) also failed to detect variation in the TLR2 promoter region.
Mikita et al. (2009) investigated the R677W polymorphism in 99 Japanese leprosy patients, whose genetic background is close to that of the Korean patients studied by Kang and Chae (2001). They found that R677W was undetectable in the Japanese patients, similar to the findings in Indian patients reported by Malhotra et al. (2005). Moreover, they failed to detect any of 7 additional nonsynonymous SNPs in the TLR2 gene in the Japanese patients.
Bochud et al. (2008) analyzed 3 TLR2 polymorphisms for associations with risk of developing leprosy, leprosy type, or leprosy reactions in 441 patients and 187 controls belonging to 3 Ethiopian ethnic groups. They found that a synonymous 597C-T SNP was associated with reduced susceptibility to reversal reaction (OR of 0.34), whereas patients homozygous for a 280-bp microsatellite marker had an increased risk of reversal reaction (OR of 5.83).
Susceptibility to Mycobacterium Tuberculosis
Using a retrospective case-control study of 151 tuberculosis (TB; see 607948) patients and 116 controls in Turkey, Ogus et al. (2004) found an increased risk of TB in carriers of a nonsynonymous 2258G-A SNP in the TLR2 gene, which causes an arg753-to-gln (R753Q; 603028.0003) substitution. The risk of developing TB was 6.0-fold and 1.6-fold higher in AA homozygotes and GA heterozygotes, respectively. Ogus et al. (2004) concluded that the R753Q substitution in TLR2 may influence susceptibility to and severity of TB disease.
Other Associations
Schroder et al. (2005) found that monocytes and lymphocytes from healthy subjects produced more TNF and IFNG, respectively, in response to high concentrations of Borrelia lysate than did healthy subjects heterozygous for the R753Q SNP. The R753Q SNP was present at significantly lower frequency in 155 Lyme disease patients, particularly those with severe disease, compared with 349 controls. Tlr2 +/- mice did not differ from wildtype mice in Tnf production when bone marrow macrophages were stimulated with LTA or LPS, but they showed significantly lower Tnf production when stimulated with Borrelia lysate. Schroder et al. (2005) concluded that the R753Q SNP may protect from development of late-stage Lyme disease due to reduced signaling via TLR2/TLR1.
Boraska Jelavic et al. (2006) studied genotype and allele frequencies of the GT microsatellite repeat polymorphism in intron 2 of the TLR2 gene (603028.0002) in sporadic colorectal cancer patients and controls and found that the frequency of TLR2 alleles with 20 and 21 GT repeats was decreased, whereas the frequency of the allele with 31 GT repeats was increased in patients versus controls.
Takeuchi et al. (2000) showed that Tlr2- and, particularly, Myd88-deficient mice are highly susceptible, in terms of growth in blood and kidney and decreased survival, to infection with Staphylococcus aureus compared to wildtype mice. In vitro, Tlr2-deficient macrophages produced reduced TNF and IL6 in response to S. aureus compared to wildtype or Tlr4-deficient macrophages, whereas Myd88-deficient macrophages produced no detectable TNF or IL6. The authors concluded that TLR2 and MYD88 are critical in the defense against gram-positive bacteria.
Using in situ hybridization, Wolfs et al. (2002) detected constitutive expression of Tlr2 and Tlr4 in mouse proximal and distal tubular renal epithelial cells. To gain insight into the regulation of TLR expression during inflammation, the authors used a mouse model of renal inflammation. During kidney inflammation, mRNA for both receptors was enhanced by TNFA and IFNG, with expression mainly localized in distal tubules, the thin limb of the loop of Henle, and collecting ducts. Western blot analysis showed enhanced renal Tlr4 expression. Wolfs et al. (2002) suggested that epithelial-derived TLR signaling has a role in the inflammatory response during ascending urinary tract infection.
Supajatura et al. (2002) examined cytokine production by bone marrow-derived mast cells from mice deficient in either Tlr2 or Tlr4. Peptidoglycan (PGN) stimulated mast cells to produce Tnf, Il4, Il5 (147850), Il6, and Il13 (147683), but not Il1b, in a Tlr2-dependent manner. In contrast, LPS stimulated mast cells to produce Tnf, Il1b, Il6, and Il13, but not Il4 or Il5, in a Tlr4-dependent manner. Tlr2- but not Tlr4-dependent mast cell stimulation resulted in mast cell degranulation and calcium mobilization. Infection of Tlr4 -/- mice by cecal ligation and puncture revealed the necessity of Tlr4-mediated peritoneal mast cell activation and neutrophil recruitment for protection from gram-negative bacterial infection. Intradermal injection of PGN led to increased vasodilation and inflammation through Tlr2-mediated activation of skin mast cells, suggesting that Tlr2-dependent skin mast cell activation may exacerbate the inflammatory lesions of atopic dermatitis, in which gram-positive bacterial infection is common.
Shishido et al. (2003) found that Tlr2-deficient mice survived longer than wildtype mice after induced myocardial infarction. There was no difference in inflammation or infarct size between knockout mice and wildtype mice. However, myocardial fibrosis in the noninfarct area of knockout mice was much less than in wildtype mice and was accompanied by reduced Tgfb1 and collagen type I (see COL1A1; 120150) mRNA expression. Left ventricular dimensions at end diastole were smaller in knockout mice than wildtype mice. Shishido et al. (2003) concluded that TLR2 plays an important role in ventricular remodeling after myocardial infarction.
To examine whether Toll-like receptor signaling regulates phagocytosis, Blander and Medzhitov (2004) compared macrophages from wildtype, Myd88 null, and Tlr2-Tlr4 double-null mice. Myd null and Tlr2-Tlr4 double-null macrophages were unresponsive to inactivated E. coli. Blander and Medzhitov (2004) found that activation of the Toll-like receptor signaling pathway by bacteria, but not apoptotic cells, regulated phagocytosis at multiple steps including internalization and phagosome maturation. Phagocytosis of bacteria was impaired in the absence of Toll-like receptor signaling. Two modes of phagosome maturation were observed, constitutive and inducible; their differential engagement depended on the ability of the cargo to trigger Toll-like receptor signaling.
Bornstein et al. (2004) found that Tlr2 -/- mice had reduced plasma corticosterone levels and marked cellular alterations in adrenocortical tissues. Radioimmunoassays showed that the mutant mice had reduced plasma corticosterone after challenge with lipoteichoic acid of Staphylococcus aureus or lipopolysaccharide, but they had no reduction in ACTH levels. The lower levels appeared to be mediated by lower systemic and intraadrenal expression of Il1 (see IL1B; 147720), Tnf, and Il6. Bornstein et al. (2004) concluded that there is a link between the innate immune system and the endocrine stress response, particularly during inflammation and sepsis. They suggested that tests of adrenal function are important in patients with TLR polymorphisms and inflammatory disease.
Hoebe et al. (2005) showed in mice that an N-ethyl-N-nitrosourea-induced nonsense mutation in Cd36 (173510) causes a recessive immunodeficiency phenotype (oblivious) in which macrophages are insensitive to the R-enantiomer of MALP2 (a diacylated bacterial lipopeptide) and to lipoteichoic acid (LTA). Both MALP2 and LTA are Tlr 2/6-dependent microbial stimuli. Homozygous mice are hypersusceptible to Staphylococcus aureus infection. Cd36(oblivious) macrophages readily detect S-MALP2, synthetic acylated lipopeptides, and zymosan, revealing that some, but not all, TLR2 ligands are dependent on CD36. The results showed that CD36 is a selective and nonredundant sensor of microbial diacylglycerides that signal through the TLR2/6 heterodimer.
In atherosclerosis-susceptible Ldlr (606945)-null mice, Mullick et al. (2005) demonstrated that complete deficiency of Tlr2 led to a reduction in atherosclerosis whereas intraperitoneal injection of a synthetic TLR2/TLR1 agonist dramatically increased atherosclerosis. In Ldlr-null mice, transplantation of Tlr2 -/- bone marrow (BM) cells had no effect on atherosclerosis, suggesting the presence of an endogenous TLR2 agonist activating TLR2 in cells that were not of BM cell origin. In Ldlr-null mice, complete deficiency of Tlr2 as well as a deficiency of Tlr2 only in BM-derived cells led to striking protection against agonist-mediated atherosclerosis, suggesting a role for BM-derived cell expression of TLR2 in transducing the effects of an exogenous TLR2 agonist. Mullick et al. (2005) stated that these findings support the concept that chronic or recurrent microbial infections contribute to atherosclerotic disease and also suggest the presence of host-derived endogenous TLR2 agonists.
Hyaluronan, an extracellular matrix glycosaminoglycan with a repeating disaccharide structure, is produced after tissue injury, and impaired clearance results in unremitting inflammation. Jiang et al. (2005) noted that CD44 (107269) is essential for regulating turnover of hyaluronan, but it is not required for expression of chemokines by macrophages after lung injury. Using Tlr-deficient mouse macrophages, they found that hyaluronan fragments stimulated Mip2 (CXCL2; 139110), Mip1a (CCL3; 182283), and Kc (CXCL1; 155730) in a Tlr2- and Tlr4-dependent manner that also required Myd88. Mice deficient in Tlr2, Tlr4, or Myd88 showed impaired transepithelial migration of inflammatory cells, but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell overexpression of high molecular mass hyaluronan protected against acute lung injury and apoptosis, in part, through TLR-dependent basal activation of NFKB. Jiang et al. (2005) concluded that interaction of TLR2 and TLR4 with hyaluronan provides signals that initiate inflammatory responses, maintain epithelial cell integrity, and promote recovery from acute lung injury.
Darville et al. (2003) found that peritoneal macrophages from Tlr2 -/- mice produced significantly less Tnf and Il6 than wildtype cells in response to the mouse pneumonitis strain of Chlamydia trachomatis. In contrast, macrophages from Tlr4 -/- mice produced more Tnf and Il6 than wildtype cells in response to C. trachomatis. Likewise, infected lung fibroblasts from Tlr2 -/- mice expressed less mRNA for Il1, Il6, and Mip2 than controls, whereas Tlr4 -/- cells expressed more mRNA for these cytokines than controls. The course of genital tract infection in Tlr2 -/- and wildtype mice was similar, but Tlr2 -/- mice secreted less Tnf and Mip2 early after infection and had significantly less oviduct and mesosalpinx pathology at later time points. Darville et al. (2003) concluded that TLR2 is an important mediator of the innate immune response to C. trachomatis infection.
Using confocal microscopy, Rolls et al. (2007) detected Tlr2 expression in the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus in adult mice. Mice lacking Tlr2 had fewer Dcx (300121)-expressing adult hippocampal neural progenitor cells (NPCs), and Tlr2 appeared to be required for differentiation of NPCs into neurons via a Myd88- and Nfkb-dependent pathway. NPCs also expressed Tlr4, but inhibition of Tlr4 expression or deletion of Tlr4 increased sphere formation, clonal efficiency, and NPC differentiation via both Myd88-dependent and -independent pathways. Rolls et al. (2007) concluded that TLR2 and TLR4 are both involved in adult neurogenesis, with TLR2 primarily involved in cell fate determination and TLR4 primarily involved in neural stem cell self-renewal.
Using a mouse model of mucosal Candida albicans infection, Hise et al. (2009) showed that Tlr2 and dectin-1 (CLEC7A; 606264) controlled Il1b transcription, whereas Nlrp3 (606416), Asc (PYCARD; 606838), and Casp1 (147678) regulated processing of pro-Il1b into the active, mature 17-kD protein. Tlr2, dectin-1, and the Nlrp3 inflammasome were essential for defense against disseminated infection and mortality in vivo.
Spurthi et al. (2018) found that Tlr2 -/- mice developed age-dependent, gender-independent cardiac remodeling and contractile dysfunction compared with wildtype. Tlr2 deficiency activated the fetal gene program and induced cardiac fibrosis, cardiac cell death, and muscle wasting in an aging-dependent manner. Tlr2-deficient hearts had reduced macrophages and neutrophils, even though these cells had increased expression of cell adhesion molecules. Western blot analysis showed increased expression of Tlr1 and endogenous Tlr ligands in Tlr2 -/- mice compared with wildtype, but this likely compensatory effect was not sufficient to rescue the defects in Tlr2 -/- hearts. Tlr2 deficiency impaired Akt activity and enhanced Foxo (see 136533) transcriptional activity to induce expression of genes involved in cardiac atrophy and cell death. Inhibition of Foxo rescued the phenotype of Tlr2 -/- cardiomyocytes and Tlr2 -/- mice, demonstrating that hyperactivation of Foxo transcription factors caused the aging-related cardiac remodeling and contractile dysfunction. In wildtype mice, Tlr2 expression decreased with aging, and activation of Tlr signaling improved contractile function of aged mice.
Kang and Chae (2001) identified a C-to-T polymorphism at nucleotide 2029 of the TLR2 gene, resulting in an arg677-to-trp change (R677W), in 10 (22%) of 45 Korean lepromatous leprosy (LPRS3; 246300) patients, but not in any of 41 Korean tuberculoid patients or 45 Korean controls. They concluded that the R677W polymorphism in the intracellular domain of TLR2 has a role in susceptibility to lepromatous leprosy.
Bochud et al. (2003) found that wildtype TLR2 mediated CD14 (158120)-enhanced Mycobacterium leprae-dependent activation of NFKB (see 164011), but TLR2 containing R677W did not. They concluded that the impaired function of the R677W variant provides a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy.
Malhotra et al. (2005) used a case control study to investigate whether the R677W SNP in TLR2 reported by Kang and Chae (2001) was associated with leprosy susceptibility in 286 Indian leprosy patients and 183 ethnically matched controls. Genotyping with the primer pair used by Kang and Chae (2001) showed heterozygosity at nucleotide 2029, leading to R677W, and at 2 other sites leading to amino acid changes in all patients and controls. In silico analysis revealed a duplicated region 23 kb upstream of TLR2 that shares 93% identity with exon 3 of TLR2 and includes the same 3 substitutions observed in the patients and controls. Genotyping using a second primer pair specific for the authentic TLR2 exon 3 showed the absence of these 3 substitutions, including R677W, in all patients and controls studied. Malhotra et al. (2005) concluded that the R677W polymorphism reported by Kang and Chae (2001) as associated with leprosy is not a true polymorphism of TLR2, but rather resulted from variation present in the upstream duplicated region.
To examine the possibility that the conflicting results of Kang and Chae (2001) and Malhotra et al. (2005) reflect different genetic backgrounds among races, Mikita et al. (2009) investigated the R677W polymorphism in 99 Japanese leprosy patients, whose genetic background is close to that of the Korean patients studied by Kang and Chae (2001). They found that R677W was undetectable in the Japanese patients, similar to the findings in Indian patients reported by Malhotra et al. (2005).
Boraska Jelavic et al. (2006) studied genotype and allele frequencies of the GT microsatellite repeat polymorphism in intron 2 of the TLR2 gene in 89 Croatian patients with sporadic colorectal cancer (see 114500) and 88 Croatian sex- and age-matched controls. The frequency of TLR2 alleles with 20 and 21 GT repeats was decreased (p = 0.0044 and p = 0.001, respectively) and the frequency of the allele with 31 GT repeats was increased (p = 0.0147) in patients versus controls.
Using a retrospective case-control study of 151 tuberculosis (TB; see 607948) patients and 116 controls in Turkey, Ogus et al. (2004) found an increased risk of TB in carriers of a nonsynonymous 2258G-A SNP in the TLR2 gene, which causes an arg753-to-gln (R753Q) substitution. The risk of developing TB was 6.0-fold and 1.6-fold higher in AA homozygotes and GA heterozygotes, respectively. Ogus et al. (2004) concluded that the R753Q substitution in TLR2 may influence susceptibility to and severity of TB disease.
Schroder et al. (2005) found that monocytes and lymphocytes from healthy subjects produced more TNF (191160) and IFNG (147570), respectively, in response to high concentrations of Borrelia lysate than did healthy subjects heterozygous for the R753Q SNP. The R753Q SNP was present at significantly lower frequency in 155 Lyme disease patients, particularly those with severe disease, compared with 349 controls. Tlr2 +/- mice did not differ from wildtype mice in Tnf production when bone marrow macrophages were stimulated with LTA or LPS, but they showed significantly lower Tnf production when stimulated with Borrelia lysate. Schroder et al. (2005) concluded that the R753Q SNP may protect from development of late-stage Lyme disease due to reduced signaling via TLR2/TLR1.
By transfecting human embryonic kidney cells with wildtype TLR2 and TLR2 with the R753Q polymorphism, Xiong et al. (2012) showed that there was little difference in cell surface expression. However, TLR2 with R753Q was compromised in its ability to activate NFKB (see 164011). Molecular modeling studies suggested that R753Q changes the electrostatic potential of the asp-asp (DD) loop within the TIR domain of TLR2, possibly affecting TLR2 dimerization with TLR1 (601194) and/or TLR6 (605403), as well as recruitment of the adaptor proteins MAL (TIRAP; 606252) and MYD88 (602170). Biochemical assays confirmed these hypotheses, demonstrating that TLR2 with R753Q exhibited deficient agonist-induced tyr phosphorylation, heterodimerization with TLR6, and recruitment of MAL and MYD88. These proximal signaling deficiencies correlated with impaired p38 (MAPK14; 600289) phosphorylation, NFKB activation, and IL8 (146930) expression in response to M. tuberculosis antigens. Xiong et al. (2012) concluded that the compromised signaling capacity of the TLR2 R753Q polymorphism results from impaired tyrosine phosphorylation, TLR6 dimerization, and MAL and MYD88 recruitment.
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