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

Li, Haixia; Liu, Shan; Han, Jinming; Li, Shengxian; Gao, Xiaoyan; Wang, Meng; Zhu, Jie; Jin, Taiyi

doi:10.3389/fimmu.2021.777606

Cited by 17 publications

(13 citation statements)

References 218 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As current treatments for HIV NCIs only attenuate the symptoms, elucidating any potential mechanism(s) of TLR-mediated neuroinflammation in the CNS of PLWH may be important for the development of therapeutics to prevent NCI not only in HAND, but also in other neurodegenerative diseases. Indeed, the targeting of TLRs and their downstream signalling pathways as a potential therapeutic approach has already demonstrated efficacy in animal models of several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, by suppressing microglia activation and neuroinflammation [83][84][85]. As IRAK1 is a key component of both IL-1R and TLR-mediated signalling, the pharmacological inhibition of IRAK1 thus has potential Each symbol represents the mean of an individual biological replicate performed in triplicate; small horizontal lines indicate the grand means of four biological replicates±sd.…”

Section: Discussionmentioning

confidence: 99%

IRAK1 inhibition blocks the HIV-1 RNA mediated pro-inflammatory cytokine response from microglia

Campbell

Rawat

Teodorof‐Diedrich

et al. 2023

Journal of General Virology

View full text Add to dashboard Cite

Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are a common source of morbidity in people living with HIV (PLWH). Although antiretroviral therapy (ART) has lessened the severity of neurocognitive disorders, cognitive impairment still occurs in PLWH receiving ART. The pathogenesis of HAND is likely multifaceted, but common factors include the persistence of HIV transcription within the central nervous system, higher levels of pro-inflammatory cytokines in the cerebrospinal fluid, and the presence of activated microglia. Toll-like receptor (TLR) 7 and TLR8 are innate pathogen recognition receptors located in microglia and other immune and non-immune cells that can recognise HIV RNA and trigger pro-inflammatory responses. IL-1 receptor-associated kinase (IRAK) 1 is key to these signalling pathways. Here, we show that IRAK1 inhibition inhibits the TLR7 and TLR8-dependent pro-inflammatory response to HIV RNA. Using genetic and pharmacological inhibition, we demonstrate that inhibition of IRAK1 prevents IRAK1 phosphorylation and ubiquitination, and the subsequent recruitment of TRAF6 and the TAK1 complex to IRAK1, resulting in the inhibition of downstream signalling and the suppression of pro-inflammatory cytokine and chemokine release.

show abstract

Section: Discussionmentioning

confidence: 99%

IRAK1 inhibition blocks the HIV-1 RNA mediated pro-inflammatory cytokine response from microglia

Campbell

Rawat

Teodorof‐Diedrich

et al. 2023

Journal of General Virology

View full text Add to dashboard Cite

show abstract

“…GWAS also uncovered that up to 10.5% of the genetic variance underlying MS risk is linked to human leukocyte antigen (HLA) class II alleles among all ethnic groups studied [29]. However, studies have also revealed that non-HLA loci and their SNPs may influence susceptibility to MS, especially those involved in controlling components involved in innate and adaptive immune responses; for instance, cytokines and TLRs [12,16,30,31].…”

Section: Discussionmentioning

confidence: 99%

“…Dysregulated expression of TLRs has been shown to correlate with immune imbalances, suggesting an increased risk of inflammatory and autoimmune diseases, and similar evidence has been indicated in neuroimmune diseases. Besides, the potential of TLRs as therapeutic targets in these diseases has been suggested [11,12]. In MS, studies have indicated that TLRs play a critical role in pathogenesis of disease; for instance, TLR3 and TLR4 expression was shown to be significantly upregulated in MS lesions, and both TLRs were positively correlated with MS pathogenesis, particularly in patients with RRMS [13].…”

Section: Introductionmentioning

confidence: 99%

Toll-like receptor 10 gene polymorphism and risk of multiple sclerosis among Iraqi patients

Atiyah

Fadhil

Ad’hiah

2022

Egypt J Med Hum Genet

View full text Add to dashboard Cite

Background Toll-like receptors (TLRs) are a family of 10 pattern recognition receptors (TLR1–TLR10) involved in the regulation of inflammatory and immune responses besides their role in the pathogenesis of autoimmune diseases including multiple sclerosis (MS). TLR10 is the least studied TLR in MS, and data for single nucleotide polymorphisms (SNPs) of the TLR10 gene are limited. Therefore, a case–control study was performed on 85 patients with relapsing–remitting MS and 86 healthy controls (HC) to explore SNPs in the promoter region of TLR10 gene. A 927-bp region was amplified, and Sanger sequencing identified 10 SNPs with a minor allele frequency ≥ 10% (rs200395112 T/A, rs201802754 A/T, rs201228097 T/A, rs113588825 G/A, rs10004195 T/A, rs10034903 C/G, rs10012016 G/A/C, rs10012017 G/T, rs33994884 T/Deletion [Del] and rs28393318 A/G). Results Del allele and T/Del genotype of rs33994884, as well as AG genotype of rs28393318, showed significantly lower frequencies in MS patients compared to HC. Allele and genotype frequencies of the 10 SNPs showed no significant differences between MS patients classified according to the Expanded Disability Status Scale. Haplotype analysis revealed that haplotype A-T-A-G-A-G-G-T-A showed a significantly increased frequency in MS patients compared to HC (odds ratio [OR] = 9.70; 95% confidence interval [CI] = 1.28–73.31; corrected probability [pc] = 0.03), while frequency of A-T-A-G-T-C-A-T-G haplotype was significantly decreased (OR = 0.10; 95% CI = 0.01–0.85; pc = 0.05). Conclusions The study indicated that two SNPs may influence susceptibility to MS (rs33994884 and rs28393318), but haplotype analysis of TLR10 gene SNPs was more informative.

show abstract

“…OxS was found to be associated with mitochondrial dysfunction, dysregulation of axonal bioenergetics and iron accumulation in the brain ( Adamczyk and Adamczyk-Sowa, 2016 ). Recent research has shown that TLRs play a crucial role in the pathogenesis and progression of neuroimmune diseases by triggering an inflammatory response ( Li et al, 2021 ). The expression of TLR3 and TLR4 was significantly increased in the center of MS lesions and around inflamed vessels in human postmortem brain tissues ( Bsibsi et al, 2002 ).…”

Section: Non-communicable Diseases Caused By Smoking: Dysregulation O...mentioning

confidence: 99%

Pathogenesis of (smoking-related) non-communicable diseases—Evidence for a common underlying pathophysiological pattern

Köpp¹

2022

Front. Physiol.

View full text Add to dashboard Cite

Non-communicable diseases, like diabetes, cardiovascular diseases, cancer, stroke, chronic obstructive pulmonary disease, osteoporosis, arthritis, Alzheimer’s disease and other more are a leading cause of death in almost all countries. Lifestyle factors, especially poor diet and tobacco consumption, are considered to be the most important influencing factors in the development of these diseases. The Western diet has been shown to cause a significant distortion of normal physiology, characterized by dysregulation of the sympathetic nervous system, renin-angiotensin aldosterone system, and immune system, as well as disruption of physiological insulin and oxidant/antioxidant homeostasis, all of which play critical roles in the development of these diseases. This paper addresses the question of whether the development of smoking-related non-communicable diseases follows the same pathophysiological pattern. The evidence presented shows that exposure to cigarette smoke and/or nicotine causes the same complex dysregulation of physiology as described above, it further shows that the factors involved are strongly interrelated, and that all of these factors play a key role in the development of a broad spectrum of smoking-related diseases. Since not all smokers develop one or more of these diseases, it is proposed that this disruption of normal physiological balance represents a kind of pathogenetic “basic toolkit” for the potential development of a range of non-communicable diseases, and that the decision of whether and what disease will develop in an individual is determined by other, individual factors (“determinants”), such as the genome, epigenome, exposome, microbiome, and others. The common pathophysiological pattern underlying these diseases may provide an explanation for the often poorly understood links between non-communicable diseases and disease comorbidities. The proposed pathophysiological process offers new insights into the development of non-communicable diseases and may influence the direction of future research in both prevention and therapy.

show abstract

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

Cited by 17 publications

References 218 publications

IRAK1 inhibition blocks the HIV-1 RNA mediated pro-inflammatory cytokine response from microglia

IRAK1 inhibition blocks the HIV-1 RNA mediated pro-inflammatory cytokine response from microglia

Toll-like receptor 10 gene polymorphism and risk of multiple sclerosis among Iraqi patients

Pathogenesis of (smoking-related) non-communicable diseases—Evidence for a common underlying pathophysiological pattern

Contact Info

Product

Resources

About