TLR Polymorphisms in FMF: Association of TLR-2 (Arg753Gln) and TLR-4 (Asp299Gly, Thre399Ile) Polymorphisms and Myeloid Cell TLR-2 and TLR-4 Expression with the Development of Secondary Amyloidosis in FMF

Soylu, Alper; Ateş, Halil; Cingoz, Sultan; Türkmen, Mehmet; Demir, Belde Kasap; Tunca, Mehmet; Sakızlı, Meral; Ci̇ri̇t, Mustafa; Ersoy, Rifki; Ülgenalp, Ayfer; Kavukçu, Salìh

doi:10.1007/s10753-010-9245-9

Cited by 10 publications

(5 citation statements)

References 24 publications

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“…Of note, we observed comparable levels of total and cell surface-associated WT and R753Q TLR2 proteins in macrophages, indicating that the effects of the R753Q SNP are not due to lower expression of the mutant TLR2. These results are consistent with conclusions obtained while studying the effect of the R753Q TLR2 SNP on manifestations of amyloidosis in patients with familial Mediterranean fever (43) and with our previous findings in HEK293 transfectants (30). However, there is a possibility that the R753Q SNP could affect dynamic trafficking of TLR2 between the plasma membrane, The results of five (WT and R753Q TLR2) and four (TLR2 KO) individual mice for each genotype are depicted.…”

Section: Discussionsupporting

confidence: 91%

The R753Q polymorphism in Toll-like receptor 2 (TLR2) attenuates innate immune responses to mycobacteria and impairs MyD88 adapter recruitment to TLR2

Pattabiraman

Panchal

Medvedev

2017

Journal of Biological Chemistry

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Toll-like receptor 2 (TLR2) plays a critical role in host defenses against mycobacterial infections. The R753Q TLR2 polymorphism has been associated with increased incidence of tuberculosis and infections with non-tuberculous mycobacteria in human populations, but the mechanisms by which this polymorphism affects TLR2 signaling are unclear. In this study, we determined the impact of the R753Q TLR2 polymorphism on macrophage sensing of Upon infection with, macrophages from knock-in mice harboring R753Q TLR2 expressed lower levels of TNF-α, IL-1β, IL-6, and IL-10 compared with cells from WT mice, but both R753Q TLR2- and WT-derived macrophages exhibited comparable bacterial burdens. The decreased cytokine responses in R753Q TLR2-expressing macrophages were accompanied by impaired phosphorylation of IL-1R-associated kinase 1 (IRAK-1), p38, ERK1/2 MAPKs, and p65 NF-κB, suggesting that the R753Q TLR2 polymorphism alters the functions of the myeloid differentiation primary response protein 88 (MyD88)-IRAK-dependent signaling axis. Supporting this notion, HEK293 cells stably transfected with YFP-tagged R753Q TLR2 displayed reduced recruitment of MyD88 to TLR2, decreased NF-κB activation, and impaired IL-8 expression upon exposure to Collectively, our results indicate that the R753Q polymorphism alters TLR2 signaling competence, leading to impaired MyD88-TLR2 assembly, reduced phosphorylation of IRAK-1, diminished activation of MAPKs and NF-κB, and deficient induction of cytokines in macrophages infected with.

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Section: Discussionsupporting

confidence: 91%

The R753Q polymorphism in Toll-like receptor 2 (TLR2) attenuates innate immune responses to mycobacteria and impairs MyD88 adapter recruitment to TLR2

Pattabiraman

Panchal

Medvedev

2017

Journal of Biological Chemistry

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“…One study showed no significant changes in expression levels of TLR2 in healthy volunteers and patients with familial Mediterranean fever expressing WT and R753Q TLR2 (70). In contrast, another group found lower ␣-CD3 Ab-inducible expression of R753Q versus WT TLR2 in T cells obtained from healthy volunteers or patients with atopic dermatitis, with distinct modulation of WT and R753Q TLR2 levels upon stimulation with lipoteichoic acid (69).…”

Section: Discussionmentioning

confidence: 98%

R753Q Polymorphism Inhibits Toll-like Receptor (TLR) 2 Tyrosine Phosphorylation, Dimerization with TLR6, and Recruitment of Myeloid Differentiation Primary Response Protein 88

Xiong

Song

Snyder

et al. 2012

Journal of Biological Chemistry

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Background: TLR2 SNPs are linked to tuberculosis, but the mechanisms by which they alter TLR signaling are unclear. Results: R753Q TLR2 showed impaired tyrosine phosphorylation, dimerization with TLR6, MyD88 recruitment, and induction of NF-B and cytokines upon mycobacterial challenge. Conclusion: R753Q polymorphism blocks TLR2 tyrosine phosphorylation and signalosome assembly. Significance: Deciphering how SNPs alter TLR signaling advances TLR immunobiology and facilitates design of new therapeutic strategies.

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“…Ozen et al hypothesized that in FMF patients TLR polymorphisms may lead to decreased responsiveness to microorganisms in order to balance the overactive innate immune system [14]. Soylu et al reported that among FMF patients, there was a prominent expression of TLR4 gene in granulocytes induced by lipopolysaccharide (LPS); however, blood or urine cultures failed to document the presence of an infection during the attacks [17]. Among our FMF patients, blood cultures and throat swab collections were sterile.…”

Section: Discussionmentioning

confidence: 86%

“…In this study, we investigated whether TLR2 and TLR4 gene expressions have a role on the trigger of attacks in patients [14,15,17]. Until now, much of the concern has been based on genetic polymorphisms of TLRs.…”

Section: Discussionmentioning

confidence: 99%

“…Apart from the studies on any association of TLR gene polymorphisms with FMF attacks, we assessed mRNA expression patterns during FMF attacks and attack-free periods [17]. In a study involving 169 FMF Greek patients, there was lower expression of TLR4-D299G in FMF patients, and there was no association between the frequency of attacks and development of amyloidosis [15].…”

Section: Discussionmentioning

confidence: 99%

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TLR2 and TLR4 gene expression levels and associated factors during acute attack and attack-free periods in familial Mediterranean fever

et al. 2014

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The purpose of this clinical study was to determine if the expression of the TLR2 and/or TLR4 genes is involved in triggering the auto-inflammatory attacks in patients with familial Mediterranean fever (FMF). Thirty patients with FMF and 20 healthy control subjects were recruited. Comparisons were made in TLR2 and TLR4 gene expression levels during FMF attack episodes and attack-free periods, as well as with baseline levels in healthy control subjects. There was no significant difference in TLR2 and TLR4 gene expression between the attacks and attack-free periods in the entire group of FMF patients. However, among female patients, expression level of TLR4 gene was significantly higher during the attack than in the attack-free period (TLR2 Log 2.04 ± 0.14 vs. 2.52 ± 0.10, respectively, P = 0.02). There was not a significant difference between FMF patients and healthy subjects. The patients who had higher levels of TLR2 expression during the acute attack experienced their first attacks at an earlier age (r = -0.571; P = 0.001). The frequency of attacks, acute-phase response, MEFV mutations, and colchicine response were not associated with TLR2 and TLR4 levels. We conclude that changes in the expression of TLR2 and TLR4 genes do not appear to be involved in triggering FMF attacks. A higher level of TLR2 expression during acute attack may be related to the early onset of the disease. Further studies using specific cell populations such as neutrophils, monocytes, and dendritic cells may be useful to explore any changes in the sensitivity of toll-like receptors to their agonists, such as lipopolysaccharides, in the onset of attacks.

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TLR Polymorphisms in FMF: Association of TLR-2 (Arg753Gln) and TLR-4 (Asp299Gly, Thre399Ile) Polymorphisms and Myeloid Cell TLR-2 and TLR-4 Expression with the Development of Secondary Amyloidosis in FMF

Cited by 10 publications

References 24 publications

The R753Q polymorphism in Toll-like receptor 2 (TLR2) attenuates innate immune responses to mycobacteria and impairs MyD88 adapter recruitment to TLR2

The R753Q polymorphism in Toll-like receptor 2 (TLR2) attenuates innate immune responses to mycobacteria and impairs MyD88 adapter recruitment to TLR2

R753Q Polymorphism Inhibits Toll-like Receptor (TLR) 2 Tyrosine Phosphorylation, Dimerization with TLR6, and Recruitment of Myeloid Differentiation Primary Response Protein 88

TLR2 and TLR4 gene expression levels and associated factors during acute attack and attack-free periods in familial Mediterranean fever

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