TLR10 (CD290) Is a Regulator of Immune Responses in Human Plasmacytoid Dendritic Cells.

TLRs are the most thoroughly studied group of pattern-recognition receptors that play a central role in innate immunity. Among them, TLR10 (CD290) remains the only TLR family member without a known ligand and clearly defined functions. One major impediment to studying TLR10 is its absence in mice. A recent study on TLR10 knock-in mice demonstrated its intrinsic inhibitory role in B cells, indicating that TLR10 is a potential drug target in autoimmune diseases. In this study, we interrogated the expression and function of TLR10 in human plasmacytoid dendritic cells (pDCs). We have seen that primary human pDCs, B cells, and monocytes constitutively express TLR10. Upon preincubation with an anti-TLR10 Ab, production of cytokines in pDCs was downregulated in response to stimulation with DNA and RNA viruses. Upon further investigation into the possible mechanism, we documented phosphorylation of STAT3 upon Ab-mediated engagement of TLR10. This leads to the induction of inhibitory molecule suppressor of cytokine signaling 3 (SOCS3) expression. We have also documented the inhibition of nuclear translocation of transcription factor IFN regulatory factor 7 (IRF7) in pDCs following TLR10 engagement. Our data provide the (to our knowledge) first evidence that TLR10 is constitutively expressed on the surface of human pDCs and works as a regulator of their innate response. Our findings indicate the potential of harnessing the function of pDCs by Ab-mediated targeting of TLR10 that may open a new therapeutic avenue for autoimmune disorders.

Analysis of TLR10 gene polymorphisms in patients with rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic systemic disease characterized by inflammatory synovitis, and genetic factors play the greatest role in RA. This study aimed to investigate the relationship between Toll-like receptor 10(TLR10) gene polymorphisms and susceptibility to RA. METHODS: A total of 271 patients with RA and an equal number of healthy controls were included, and the TLR10 rs2101521, rs10004195 and rs11725309 loci were genotyped by time-of-flight mass spectrometry. RESULTS: Compared with healthy controls, Individuals carrying the rs2101521 G allele had an increased risk of developing RA (P = 0.01; odds ratio (OR) = 1.367; 95 % confidence interval (CI): 1.076-1.736). Individuals with the rs2101521 GG genotype had a greater risk of RA (P = 0.01; OR = 1.816; 95 % CI: 1.161-2.984). Stratified analysis demonstrated a greater prevalence of positive anti-cyclic citrullinated peptide (CCP)antibody in patients carrying the rs2101521 G allele (P = 0.03). Additionally, patients with the rs11725309 CT genotype had elevated levels of C-reactive protein (CRP)(P = 0.007). CONCLUSION: In conclusion, TLR10 gene polymorphisms are associated with RA susceptibility.

TLRs1-10 Protein Expression in Circulating Human White Blood Cells during Bacterial and COVID-19 Infections.

INTRODUCTION: Toll-like receptors play crucial roles in the sepsis-induced systemic inflammatory response. Septic shock mortality correlates with overexpression of neutrophilic TLR2 and TLR9, while the role of TLR4 overexpression remains a debate. In addition, TLRs are involved in the pathogenesis of viral infections such as COVID-19, where the single-stranded RNA of SARS-CoV-2 is recognized by TLR7 and TLR8, and the spike protein activates TLR4. METHODS: In this study, we conducted a comprehensive analysis of TLRs 1-10 expressions in white blood cells from 71 patients with bacterial and viral infections. Patients were divided into 4 groups based on disease type and severity (sepsis, septic shock, moderate, and severe COVID-19) and compared to 7 healthy volunteers. RESULTS: We observed a significant reduction in the expression of TLR4 and its co-receptor CD14 in septic shock neutrophils compared to the control group (p < 0.001). Severe COVID-19 patients exhibited a significant increase in TLR3 and TLR7 levels in neutrophils compared to controls (p < 0.05). Septic shock patients also showed a similar increase in TLR7 in neutrophils along with elevated intermediate monocytes (CD14+CD16+) compared to the control group (p < 0.005 and p < 0.001, respectively). However, TLR expression remained unchanged in lymphocytes. CONCLUSION: This study provides further insights into the mechanisms of TLR activation in various infectious conditions. Additional analysis is needed to assess their correlation with patient outcome and to evaluate the impact of TLR-pathway modulation during septic shock and severe COVID-19.

Indirect influence of microRNA-146a on the association of IL-6 and TNF-α genetic polymorphisms with the increased risk of hip osteoarthritis.

Primary osteoarthritis (POA) is a complex hereditary disease that involves the interplay between genetics and epigenetics. MicroRNA molecules play important roles in epigenetic mechanisms. MicroRNA-146a (miR-146a) is a negative regulator of the immune response in osteoarthritis (OA). So, variations in the miR-146a gene could affect OA risk. The aim of this study was to investigate the relationships between single nucleotide polymorphisms (SNPs) in the miR-146a, interleukin-6 (IL-6), Toll-like receptor 10 (TLR10), and tumor necrosis factor-alpha (TNFA) genes and the risk for development of advanced-stage primary hip osteoarthritis (PHOA) and primary knee osteoarthritis (PKOA) in the Croatian population. A total of 609 POA patients and 656 healthy donors were genotyped for SNPs in the miR-146a (rs2910164, G>C). Since we used same patients and controls as two studies before us, we already had information about IL-6 (rs1800795, C>G), TLR10 (rs11096957, C>T), and TNFA (rs1800629, C>T) genotypes of our subjects. None of the differences were statistically significant comparing either allelic or genotypic frequencies of miR-146a SNP rs2910164 (G>C) between the PHOA and PKOA patients and controls. However, we found a significant association with risk to PHOA for the combination of genotypes (stratified miR-146a genotype with the IL-6, and stratified miR-146a genotype with the TNFA). In a multifactorial disease such as POA, we have shown the indirect relevance of a second modifying factor (miR-146a), which apparently contributes to the overall risk of PHOA. There was no risk association with the PKOA, indicating that these two localities (hip and knee) might have different risk-modifying factors.

TLR10: An Intriguing Toll-Like Receptor with Many Unanswered Questions.

BACKGROUND: Toll-like receptors (TLRs) are one of the first pattern recognition receptors found in the innate immune system. The TLR family has 12 members (TLR1-TLR9, TLR11-TLR13) in mice and 10 members (TLR1-TLR10) in humans, with TLR10 being the latest identified. SUMMARY: Considerable research has been performed on TLRs; however, TLR10 is known as an orphan receptor for the lack of information on its signalling, role, and ligands. Even though there are recent studies pointing towards the potential TLR10 ligands, their function and signalling pathway are yet to be determined. KEY MESSAGES: This review gives an insight into recent findings on TLR10's pro- and anti-inflammatory properties, with the goal of outlining existing results and indicating future research topics on this receptor.

Relationship of Toll-Like Receptor 7, 9, and 10 Polymorphisms and the Severity of Coronavirus Disease 2019.

Coronavirus disease 2019 (COVID-19) is a pandemic that is still affecting people and has caused many deaths. Toll-like receptors (TLRs) have an important role in the binding of disease agents to the host cell, disease susceptibility and severity, and host disease resistance. In this study, we investigated the frequencies of TLR7 (C.4-151 A/G), TLR9 (T-1486C and G2848A), and TLR10 (720A/C and 992T/A) single nucleotide polymorphisms in 150 cases with COVID-19 and 171 control samples. We also examined whether TLR7, TLR9, and TLR10 were related to COVID-19 severity. Furthermore, we analyzed the association between COVID-19 and some clinical parameters. Polymerase chain reaction based on restriction fragment length polymorphisms performed for the TLR7, TLR9, and TLR10 single nucleotide polymorphisms. TLR7 C.4-151 A/G G allele and GG genotype; TLR9 T-1486C C allele and TC, CC genotypes; and TLR10 720A/C C allele; TLR10 992T/A A allele and AA genotype frequencies were statistically significant in cases with COVID-19 compared with controls (P < 0.05*). In addition, there was a statistically significant difference in the distribution of TLR7, TLR9, and TLR10 allele and genotype frequencies between the severity groups (P < 0.05*). Our findings suggest that TLR7, TLR9, and TLR10 polymorphisms may be crucial for the clinical course and susceptibility to infection.

An Update on Toll-like Receptor 2, Its Function and Dimerization in Pro- and Anti-Inflammatory Processes.

While a certain level of inflammation is critical for humans to survive infection and injury, a prolonged inflammatory response can have fatal consequences. Pattern recognition Toll-like receptors (TLRs) are key players in the initiation of an inflammatory process. TLR2 is one of the most studied pattern recognition receptors (PRRs) and is known to form heterodimers with either TLR1, TLR4, TLR6, and TLR10, allowing it to recognize a wide range of pathogens. Although a large number of studies have been conducted over the past decades, there are still many unanswered questions regarding TLR2 mechanisms in health and disease. In this review, we provide an up-to-date overview of TLR2, including its homo- and heterodimers. Furthermore, we will discuss the pro- and anti-inflammatory properties of TLR2 and recent findings in prominent TLR2-associated infectious and neurodegenerative diseases.

Toll-like receptor 10 is down-regulated in serum of patients with relapsing-remitting multiple sclerosis but not associated with Epstein-Barr virus.

In this study, toll-like receptor 10 (TLR10) and Epstein-Barr virus (EBV) were determined in the peripheral blood of 43 patients with relapsing-remitting multiple sclerosis and 41 age- and gender-matched controls. Serum TLR10 levels were assessed using an enzyme-linked immunosorbent assay kit. EBV DNA and viral load were detected using a real-time polymerase chain reaction assay kit. Results revealed that median TLR10 levels were significantly lower in patients than in controls (318 vs. 574 pg/mL; p < 0.001). Most patients were classified as low producers of TLR10 (≤ median of controls) compared to controls (84.0 vs. 51.0%; p < 0.001). Logistic regression analysis revealed that participants with low TLR10 production had an odds ratio of 4.52. Receiver operating characteristic curve analysis indicated that TLR10 is a good predictor of multiple sclerosis (area under the curve = 0.778; p < 0.001). Prevalence of EBV was less frequent in patients than in controls but the difference was not significant (23.3 vs. 41.5%; p = 0.102), while median EBV load was significantly higher in patients compared to controls (8.55 vs. 1.29 DNA copy/100 cells). When TLR10 levels were stratified according to age group, gender, EBV positivity, Expanded Disability Status Scale (EDSS), or therapy, no significant differences were found in each stratum. Further, no significant correlation was found between TLR10 levels and EDSS or EBV load. In conclusions, TLR10 was down-regulated in serum of multiple sclerosis patients, and this down-regulation was not affected by age, gender, EBV load, EDSS, or therapy.

TLR10 genotypes affect long-term graft function in tacrolimus-treated solid organ transplant recipients.

The present study was conducted to investigate the relationship between single nucleotide polymorphisms (SNPs) in TLR10 and the clinical outcomes of renal transplant patients who took tacrolimus (TAC) as an immunosuppressant, and further confirmed the results in liver transplant patients. A total of 172 renal transplant patients and 145 pairs of liver transplant recipients and donors were included. Nineteen SNPs of TLR10 gene were detected by matrix-assisted laser desorption ionization-time-of-flight-mass spectrometry (MALDI-TOF-MS). The associations of recipient SNPs with TAC-related clinical outcomes were explored in renal transplant recipients. The relationship between recipient and donor SNPs and the clinical outcomes of liver transplant patients were investigated to confirm the results. Three SNPs (rs28393318, rs11466655 and rs11096957) in renal transplant recipients were found to influence the graft function after transplantation (P = 0.00003, 0.001 and 0.000003, respectively). The recipient rs11096957 was also found to affect the TBil, and DBil levels in liver transplant recipients (P = 0.001 and 0.002). In this study, we identified significant association signals from TLR10 polymorphisms with clinical outcomes in TAC-treated transplant patients in a Chinese Han-based sample. We provide some evidence for the effect between rs11096957 in TLR10 gene on the graft functions in both renal and liver transplantation.

Toll-like receptor 10 has a role in human macrophage response against Streptococcus pneumoniae.

Toll-like receptors (TLRs) are evolutionarily conserved pathogen-associated molecular pattern recognition receptors, and play a critical role in early response against invading pathogens. Even though TLRs have been widely studied, very little is known about the expression and function of TLR10. Till date, neither any data are available on expression of TLR10 in human lungs nor there is any information on function of TLR10 in macrophages. Streptococcus pneumoniae are Gram-positive, alpha-hemolytic, and major causative agent of pneumonia, ear infections, sinus infections, and meningitis. We examined the role of TLR10 in innate immune response to S. pneumoniae infection in U937 cell line-derived human macrophages. We found a significant increase in TLR10 mRNA and protein expression in S. pneumoniae challenged macrophages. TLR10 knockdown resulted in significant reduction of IL-1ß, IL-8, IL-17, and TNF-α but not IL-10 expression in infected macrophages. TLR10 knockdown in macrophages reduced nuclear translocation of NF-κB during S. pneumoniae challenge but did not affect the phagocytosis of the bacteria. Taken together, we report the first data on TLR10's role in macrophage response against S. pneumoniae.

Regulation of TLR10 Expression and Its Role in Chemotaxis of Human Neutrophils.

Toll-like receptors are innate immune receptors that play a critical role in pathogen-associated molecular pattern recognition. TLR10 was recently identified and very limited data are available on its expression, mechanisms that regulate its expression, and its role in primary immune cells. To study the expression pattern of TLR10 in primary immune cells, we examined TLR10 protein expression in naive and Escherichia coli lipopolysaccharide (LPS)-activated human neutrophils. Human neutrophils challenged with LPS showed a decrease in total and surface TLR10 expression at 90 min. TLR10 in LPS-activated neutrophils colocalized with flotallin-1, a lipid raft marker, and EEA-1, an early endosomal marker, to suggest its endocytosis. There was increased colocalization of TLR10 with TLR4 at LPS 60 min followed by decrease at later LPS treatment times. Treatment with TLR4 neutralizing antibody decreased cytoplasmic localization of TLR10 in LPS-treated neutrophils. Reactive oxygen species (ROS) depletion and neutralization of p65 subunit of NF-κB in LPS-treated neutrophils decreased TLR10 expression. Live cell imaging of LPS-activated neutrophils showed TLR10 translocation in the leading edge and TLR10 knockdown in neutrophils reduced their fMLP-induced chemotaxis and the number of neutrophils with pseudopodia but without affecting the expression of key proteins of actin nucleation process, ARP-3 and Diap1. Taken together, our findings show that neutrophil activation alters TLR10 expression through ROS production and NF-κB regulation, and TLR10 knockdown reduced neutrophil chemotaxis.

Toll-like receptor 10 expression in B cells is negatively correlated with the progression of primary Sjögren's disease.

Primary Sjögren's Disease (pSjD) is considered a B cell-mediated disease. Toll-like receptor 10 (TLR10) is highly expressed in human B cells, indicating that TLR10 probably plays a vital role in pSjD. We examined TLR10 expression in peripheral B subsets of pSjD patients and analyzed their association with disease activity. We observed that TLR10 expression in total, naïve, memory, and switched memory B cells was significantly increased in low-activity pSjD patients as compared with healthy controls and high-activity patients. TLR10 expression in the above mentioned B subsets (except naïve B) was negatively correlated with serum levels of anti-SSA antibody and BAFF, respectively. Moreover, a higher proportion of high-activity pSjD patients was observed in TLR10 low- than high-expressed patients. Our study concluded that TLR10 expression in CD19+ B and memory B was negatively correlated with pSjD disease activity, suggesting that TLR10 might take part in the progression of pSjD.

Gene polymorphisms of TLR10: effects on bacterial meningitis outcomes in Angolan children.

This study examined whether gene polymorphisms for toll-like receptor 10 (TLR10) associated with the susceptibility to and outcomes of bacterial meningitis (BM) in Angolan children. The study cohort consisted of 190 BM patients and the determination of ten single-nucleotide polymorphisms (SNPs) by Sanger sequencing. Patients with BM caused by Streptococcus pneumoniae who carried the following variants of TLR10 SNPs exhibited an increased risk of coexisting pneumonia: rs10004195 (T > A) (p = 0.025), rs10856837 (G > A) (p = 0.018) or rs11096956 (G > T) (p = 0.010). Yet, TLR10 SNPs rs11466652 (A > G), rs10856837 (G > A) and rs11096956 (G > T) influenced the protein levels in the cerebrospinal fluid (CSF). Moreover, compared with the wild type, patients with pneumococcal meningitis carrying a variant genotype of TLR10 SNP rs11466648 (A > G) exhibited an increased risk of developing blindness (p = 0.025), whereas patients with TLR10 SNP rs10004195 (T > A) exhibited a lower risk of convulsions at admission (p = 0.039) and a lower risk of altered consciousness (p = 0.029). This study suggests a relationship exists between coexisting pneumonia, protein levels in CSF, blindness, convulsions and an altered consciousness with genetic variations of TLR10 in BM in Angolan children.

Long noncoding RNA GAS5 inhibits LX-2 cells activation by suppressing NF-κB signalling through regulation of the miR-433-3p/TLR10 axis.

BACKGROUND: Liver fibrosis is a common disease that can lead to hepatic failure. AIMS: Our aims were to reveal the role of GAS5 in the regulation of liver fibrosis. METHODS: LX-2 human hepatic satellite cells (HSCs) were cultured and activated using TGF-ß1 treatment. A CCK-8 assay was performed to assess cell viability. A luciferase assay was employed to monitor the interactions between miR-433-3p and GAS5 or toll-like receptor 10 (TLR10). Western blotting and real-time quantitative PCR (RT-qPCR) were applied to detect the expression levels of α-SMA, Col. I, PCNA-, MMP2-, MMP9-, TLR10-, and NF-κB-related molecules at the protein and RNA levels. RESULTS: GAS5 and TLR10 were decreased while miR-433-3p was upregulated in TGF-ß1-activated LX-2 cells. Upregulation of GAS5 or downregulation of miR-433-3p suppressed HSC activation, and luciferase assays indicated that miR-433-3p binds with GAS5 and the 3'-UTR of TLR10. MiR-433-3p upregulation and TLR10 downregulation rescued the impacts of GAS5 overexpression or miR-433-3p knockdown on LX-2 cells. Upregulation of GAS5 also suppressed the phosphorylation of NF-κB through the miR-433-3p/TLR10 axis. CONCLUSION: LncRNA GAS5 exerts an inhibitory effect on HSC activation by suppressing NF-κB signalling through regulation of the miR-433-3p/TLR10 axis.

TLR10 and Its Role in Immunity.

Toll like receptors (TLRs) are the most studied pattern recognition receptors (PRRs) as they connect the innate to the acquired immune response. To date, there are ten human TLRs which are expressed either on the plasma membrane or on the endosomes. TLR1, TLR2, TLR4, TLR5, TLR6 and TLR10 are plasma membrane TLRs that recognise extracellular components of pathogens, whereas TLR3, TLR7, TLR8 and TLR9 are located on endosomes where they recognise foreign nucleic acids. Of these TLRs, TLR10 is the latest human TLR to be discovered and its function and ligands are still unclear. TLR10 is the only known member of TLR family that can elicit anti-inflammatory effect. TLR10 can inhibit other TLRs by competing with stimulatory TLRs, dimerising with TLR1, TLR2 and TLR6, and by inducing PI3K/Akt to produce IL-1Ra. There is controversy on the function of TLR10 as an anti-inflammatory TLR as initial studies on TLR10 revealed it to promote inflammation. Herein, we review the detailed functions of TLR10 in immunity and give an account of how and when TLR10 can act on both sides of the inflammatory spectrum.

Association of toll-like receptor 4, 5 and 10 polymorphisms with Helicobacter pylori-positive peptic ulcer disease in a center in Jordan.

BACKGROUND: Helicobacter pylori infection is widespread, affecting about 50% of the global population. Polymorphisms in host genes such as the toll-like receptor 4 (TLR4) might affect the susceptibility and severity of infection and treatment success. OBJECTIVE: Investigate the susceptibility and severity of H pylori infection with host TLR4 (rs11536889, rs4986790, rs200109652, rs10759932), TLR5 (rs5744174, rs2072493, rs746250566), TLR10 (rs559182335, rs10004195) polymorphisms. DESIGN: Analytical, cross-sectional. SETTING: Endoscopy clinic at tertiary care center. PATIENTS AND METHODS: Genomic DNA was extracted from formalin-fixed paraffin-embedded tissues collected from H pylori-infected patients and healthy individuals. The single nucleotide polymorphisms (SNPs) within the targeted TLR genes were genotyped to assess the genetic association of various SNPs with disease severity. MAIN OUTCOME MEASURES: Effect of genotype distribution on H pylori infection. SAMPLE SIZE: 250 peptic ulcer patients and 217 controls. RESULTS: The TLR10 genotype showed no significant association with H pylori infection except for rs10004195 (T>A) (P=.002). The genotype frequency of Rs5744174 in TLR5 had a significant association with the presence of H pylori infection (P=.046, OR=0.52). Except for gender (P=.022), there were no significant associations between clinical and demographic variables and SNPs relating to the severity of the H pylori infections. CONCLUSIONS: Our findings are consistent with differences in severity of H pylori infection due to TLR SNPs in different ethnic groups. Understanding differences in genetic susceptibility could help in classifying patients and matching patients with various treatment options on a genetic basis. LIMITATIONS: Lack of H pylori pathogenicity features assessment. CONFLICTS OF INTEREST: None.

Synergistic effect of genetic polymorphisms in TLR6 and TLR10 genes on the risk of pulmonary tuberculosis in a Moldavian population.

Polymorphisms in genes that control immune function and regulation may influence susceptibility to pulmonary tuberculosis (TB). In this study, 14 polymorphisms in 12 key genes involved in the immune response (VDR, MR1, TLR1, TLR2, TLR10, SLC11A1, IL1B, IL10, IFNG, TNF, IRAK1, and FOXP3) were tested for their association with pulmonary TB in 271 patients with TB and 251 community-matched controls from the Republic of Moldova. In addition, gene-gene interactions involved in TB susceptibility were analyzed for a total of 43 genetic loci. Single nucleotide polymorphism (SNP) analysis revealed a nominal association between TNF rs1800629 and pulmonary TB (Fisher exact test P = 0.01843). In the pairwise interaction analysis, the combination of the genotypes TLR6 rs5743810 GA and TLR10 rs11096957 GT was significantly associated with an increased genetic risk of pulmonary TB (OR = 2.48, 95% CI = 1.62-3.85; Fisher exact test P value = 1.5 × 10-5, significant after Bonferroni correction). In conclusion, the TLR6 rs5743810 and TLR10 rs11096957 two-locus interaction confers a significantly higher risk for pulmonary TB; due to its high frequency in the population, this SNP combination may serve as a novel biomarker for predicting TB susceptibility.

Toll-like receptor 10 controls TLR2-induced cytokine production in monocytes from patients with Parkinson's disease.

Peripheral inflammation, particularly mediated by monocytes, can cause neuroinflammation in Parkinson's disease (PD). We investigated the mechanism of TLR2-induced cytokine impairment in peripheral monocytes from PD patients and the association between the presence of CD14+ TLR10+ monocytes and PD severity. Peripheral blood mononuclear cells from PD patients and healthy individuals were evaluated for TLR expression on monocyte subsets (CD14 and CD16 expression) using flow cytometry. Moreover, cytokines were evaluated using flow cytometry after stimulation with Pam3 Cys (TLR2/TLR1 agonist) in the absence or presence of neutralizing antibodies to TLR10. The severity of PD was assessed using the unified PD rating scale (UPDRS) and motor activity, anxiety (BAI), depression (BDI), and fatigue (PD Fatigue Scale-16) scales. The frequency of CD14+ TLR10+ monocytes and expression intensity of TLR2 and TLR10 were higher in patients with PD than healthy individuals. The frequency of intermediate monocytes (CD14++ CD16+ ) was not significantly increased in patients with PD, but was the main monocyte subset expressing TLR10. The TLR2/TLR1-impaired cytokine production (IL-6, TNFα, IL-8, and IL-10) in PD patients was reversed by neutralizing TLR10. The high frequency of total CD14+ TLR10+ monocytes was associated with a reduction in the severity of PD according to the evaluation of motor and nonmotor symptoms. Peripheral monocytes from patients with PD showed phenotypic and functional alterations. The expression of TLR10 on monocytes can protect against PD by controlling TLR2-induced cytokine production. Furthermore, data suggested that a low frequency of CD14+ TLR10+ monocytes indicates the severity of PD. The results identified new opportunities for the development of novel PD neuroprotective therapies.

Toll-like receptor 10 rs10004195 variation may be protective against Bacillus Calmette-Guérin osteitis after newborn vaccination.

AIM: Toll-like receptor 1 (TLR1), TLR2, TLR6 and TLR10 form the TLR2 subfamily. In our previous controlled studies in 132 subjects with osteitis after newborn Bacillus Calmette-Guérin (BCG) vaccination, TLR1, TLR2 and TLR6 variations were associated with the risk of BCG osteitis. Now, we evaluated the role of ten single nucleotide polymorphisms (SNP) of the TLR10 gene in this cohort. METHODS: Five synonymous TLR10 SNPs (rs10004195, rs10856837, rs10856838, rs1109695 and rs11466652), and five missense TLR10 SNPs (rs11096955, rs11096957, rs11466649, rs11466653 and rs11466658) were determined by polymerase chain reaction (PCR)-based sequencing in 132 former BCG osteitis patients. RESULTS: TLR10 rs10004195 polymorphism was associated with the risk of BCG osteitis, compared to Finnish population controls. The variant genotype (AT/AA) was present in 13.6% of cases versus 26.2% of controls (p = 0.024). Correspondingly, the minor allele frequency (MAF) was lower (0.075) in cases than in controls (0.152; p = 0.009). There were no significant differences in the genotypes of the other nine studied TLR10 SNPs or in the corresponding MAFs between cases and controls. CONCLUSION: Among ten studied TLR10 gene polymorphisms, the variation only in the TLR10 rs10004195 was associated with the BCG osteitis risk after newborn BCG vaccination.

TLR10: Insights, controversies and potential utility as a therapeutic target.

The Toll-like receptor (TLR) family acts as a bridge connecting innate and acquired immunity. TLR10 remains one of the least understood members of this family. Some studies have examined TLR10 ligands, dimerization of TLR10 with other TLRs, and downstream signalling pathways and functions, but they have often arrived at conflicting conclusions. TLR10 can induce the production of proinflammatory cytokines by forming homodimers with itself or heterodimers with TLR1 or other TLRs, but it can also inhibit proinflammatory responses when co-expressed with TLR2 or potentially other TLRs. Mutations in the Toll/Interleukin 1 receptor (TIR) domain of TLR10 alter its signalling activity. Polymorphisms in the TLR10 gene can change the balance between pro- and anti-inflammatory responses and hence modulate the susceptibility to infection and autoimmune diseases. Understanding the full range of TLR10 ligands and functions may allow the receptor to be exploited as a therapeutic target in inflammation- or immune-related diseases. Here, we summarize recent findings on the pro- and anti-inflammatory roles of TLR10 and the molecular pathways in which it is implicated. Our goal is to pave the way for future studies of the only orphan TLR thought to have strong potential as a target in the treatment of inflammation-related diseases.