TLR-2 and TLR-4 agonists favor expansion of CD4+ T cell subsets implicated in the severity of neuromyelitis optica spectrum disorders

Dias, Aleida S.O.; Sacramento, Priscila M.; Lopes, Lana M; Sales, Marisa C.; Castro, Camilla; Araújo, Ana Carolina R.A.; Ornelas, Alice M.M.; Aguiar, Renato Santana; Silva-Filho, Renato G.; Alvarenga, Regina; Bento, Cleonice A.M.

doi:10.1016/j.msard.2019.06.018

Cited by 13 publications

(11 citation statements)

References 46 publications

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“…This supports that function of Treg cells in NMOSD is damaged (insufficient IL-10 secretion), thus leading to sustained neuroinflammation ( 107 – 110 ). Interestingly, the later study found that agonists of TLR9 induced IL-10 secretion from NMOSD-derived Treg cells, while TLR2 agonist did not ( 111 ). Paradoxically, TLR2 knockout animal model of psoriasis significantly weakened the mRNA expression of foxp-3 and IL-10, inhibited the proliferation of Treg cells and exacerbated psoriasiform skin inflammation.…”

Section: Role Of Tlrs In Neuroimmune Diseasesmentioning

confidence: 99%

“…Dias et al ( 111 ) evaluated the direct effects of different TLR ligands on CD4 + T cells form NMOSD and healthy individuals, their results suggested that the agonists of TLR2 (Pam3C), TLR4 (lipopolysaccharide) (LPS) and TLR5 (FLA), but not TLR9 (ODN), elevated CD4 + T cells expansion in NMOSD patients. As expected, Pam3C, LPS, FLA and ODN did not show the obvious CD4 + T cells proliferative activities in the healthy individuals ( 111 ). Besides, they found that all TLRs agonists induced the release of IL-6, IL-17 and IL-21 by CD4 + T cells without extra stimuli, and with TLR2 and TLR4 agonists being the most effective.…”

Section: Role Of Tlrs In Neuroimmune Diseasesmentioning

confidence: 99%

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Role of Toll-Like Receptors in Neuroimmune Diseases: Therapeutic Targets and Problems

Liu

Han

et al. 2021

Front. Immunol.

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Toll-like receptors (TLRs) are a class of proteins playing a key role in innate and adaptive immune responses. TLRs are involved in the development and progression of neuroimmune diseases via initiating inflammatory responses. Thus, targeting TLRs signaling pathway may be considered as a potential therapy for neuroimmune diseases. However, the role of TLRs is elusive and complex in neuroimmune diseases. In addition to the inadequate immune response of TLRs inhibitors in the experiments, the recent studies also demonstrated that partial activation of TLRs is conducive to the production of anti-inflammatory factors and nervous system repair. Exploring the mechanism of TLRs in neuroimmune diseases and combining with developing the emerging drug may conquer neuroimmune diseases in the future. Herein, we provide an overview of the role of TLRs in several neuroimmune diseases, including multiple sclerosis, neuromyelitis optica spectrum disorder, Guillain-Barré syndrome and myasthenia gravis. Emerging difficulties and potential solutions in clinical application of TLRs inhibitors will also be discussed.

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Section: Role Of Tlrs In Neuroimmune Diseasesmentioning

confidence: 99%

Section: Role Of Tlrs In Neuroimmune Diseasesmentioning

confidence: 99%

Role of Toll-Like Receptors in Neuroimmune Diseases: Therapeutic Targets and Problems

Liu

Han

et al. 2021

Front. Immunol.

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“…Activation of TLR4 promotes Th17 cell proliferation, migration, and the development of experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS). However, TLR4 does not appear to contribute to Th17 lineage commitment (Reynolds et al, 2012;McAleer et al, 2010;Dias et al, 2019). Importantly, activation of TLR2 directly contributes to Th17 differentiation and function (Dias et al, 2019;Reynolds et al, 2010).…”

Section: Introductionmentioning

confidence: 98%

Toll-like receptor 2 induces pathogenicity in Th17 cells and reveals a role for IPCEF in regulating Th17 cell migration

Marks¹,

Flaherty²,

Patterson³

et al. 2021

Cell Reports

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“…Neuromyelitis optica spectrum disorder (NMOSD) is a demyelinating autoimmune disease primarily affecting the spinal cord and optic nerve. Compared to multiple sclerosis, Neuromyelitis optica occurs more frequently in women than in men, by as much as ( 1 , 2 ): 1 ( 3 ). The primary outcomes are physical and visual disabilities.…”

Section: Introductionmentioning

confidence: 99%

“…However, the exact molecular mechanisms behind the pathogenesis of NMOSD remain unclear. Some studies have shown that toll-like receptor (TLR) signaling, which has been implicated in various neuroimmune processes, may play a relevant role in the pathogenesis of NMOSD ( 1 , 2 , 8 ).…”

Section: Introductionmentioning

confidence: 99%

Associations of IRAK1 Gene Polymorphisms and mRNA Expression With NMOSD Risk in the Northern Chinese Han Population

et al. 2021

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Objectives: Interleukin (IL)-1 receptor-associated kinase 1 (IRAK1) is a very important immunomodulatory gene for autoimmune diseases located on the X chromosome. However, there was little study about the correlation of IRAK1 functional single nucleotide polymorphisms with mRNA expression in neuromyelitis optica spectrum disorder (NMOSD) patients. In this study, we aimed to investigate the plausible association of IRAK1 polymorphism, IRAK1 mRNA expression, and NMOSD risk in the northern Chinese Han population.Methods: Four loci of IRAK1 gene (rs1059702, rs7061789, rs1059703, and rs3027898) were genotyped using multiplex SNaPshot technique in 102 NMOSD patients and 213 healthy subjects. Allele, genotype, and haplotype frequencies were compared. Stratified analyses were conducted by age, sex, AQP4 status, and age of onset. IRAK1 mRNA levels in the peripheral blood mononuclear cells of 30 NMOSD patients (of active phase) and 15 healthy control subjects were detected using qPCR. The correlations between the SNP polymorphisms and mRNA expression levels of genes were tested using non-parametric tests.Results: The minor allele frequencies (MAF) of these four locis were significantly lower in NMOSD cases than that of the controls. The frequencies of rs1059703G/G genotype, rs1059702A/A genotype, rs3027898 C/C genotype, and rs7061789G/G genotype were higher in the case group than that of the control group. Haplotype analysis revealed that the major haplotype “G-A-C-G” (alleles in the order of SNPs rs1059703, rs1059702, rs3027898, and rs7061789), containing the risk alleles, conferred an adverse effect on NMOSD. The level of IRAK1mRNA was markedly higher in NMOSD when compared to the healthy control groups. The IRAK1mRNA levels of female patients with the major haplotype were significantly higher compared to those with other haplotypes and to the male patients with the same genotype.Conclusion: IRAK1 polymorphisms were highly correlated with NMOSD susceptibility. Its haplotype G-A-C-G (rs1059703-rs1059702-rs3027898-rs7061789) confers increasing the risk of NMOSD in female patients. The IRAK1 risk haplotype G-A-C-G upregulated IRAK1 mRNA expression in female NMOSD patients. Our study provides a novel insight into the molecular mechanism of the pathogenesis of NMOSD and reveals that IRAK1 is the potential mechanism-specific druggable target in NMOSD disease.

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TLR-2 and TLR-4 agonists favor expansion of CD4+ T cell subsets implicated in the severity of neuromyelitis optica spectrum disorders

Cited by 13 publications

References 46 publications

Role of Toll-Like Receptors in Neuroimmune Diseases: Therapeutic Targets and Problems

Role of Toll-Like Receptors in Neuroimmune Diseases: Therapeutic Targets and Problems

Toll-like receptor 2 induces pathogenicity in Th17 cells and reveals a role for IPCEF in regulating Th17 cell migration

Associations of IRAK1 Gene Polymorphisms and mRNA Expression With NMOSD Risk in the Northern Chinese Han Population

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