Nucleic acid-sensing toll-like receptors: Important players in Sjögren’s syndrome

Alexopoulou, Lena

doi:10.3389/fimmu.2022.980400

Cited by 7 publications

(4 citation statements)

References 158 publications

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“…Therefore, this study screened datasets from primary Sjögren’s syndrome (pSS) and non-SS samples, and through bioinformatics analysis, identified 11 key genes associated with pyroptosis in SS salivary glands. Among them, the expression levels of AIM2, 30 CCL5, 32 CD274, 33 ICAM1, 34 IL18, 30 TLR8, 35 TNFSF13B 36 have been confirmed to be significantly upregulated in the SG of SS patients. Additionally, numerous studies have validated the close association of these genes with pyroptosis in SS.…”

Section: Discussionmentioning

confidence: 96%

Identification of Key Genes for Pyroptosis-Induced Salivary Gland Inflammation in Sjogren’s Syndrome Based on Microarray Data and Immunohistochemistry Analysis

Zhang,

Luo,

Zhu

et al. 2023

JIR

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Purpose Sjogren’s Syndrome (SS) is a systemic autoimmune disease primarily characterized by dysfunction of the exocrine glands. Research into the etiology and pathogenesis of salivary glands (SG) inflammation of SS is very limited. The aim of this study was to identify potential pyroptosis-related genes in SG inflammation through bioinformatics analysis and validation of the SG in SS. Methods GSE157159 dataset and GSE159574 dataset were downloaded from Gene Expression Omnibus (GEO). Differentially Expressed Genes (DEGs) analysis was used to screen DEGs from SS and non-SS SG samples. Pyroptosis-related genes were obtained from GeneCards. After intersecting DEGs with pyroptosis-related genes, the pyroptosis-related DEGs in SS were obtained. Subsequently, ClueGO enrichment analysis, Kyoto Encyclopaedia of Genes and Genomes (KEGG) enrichment analysis, Protein-protein Interaction (PPI), and identification and co-expression analysis of hub genes were performed. Subsequently, we collected SG samples from 17 SS patients and 17 non-SS patients and validated the expression of two hub genes (GZMA, GBP1) and characteristic genes (GSDMD) of pyroptosis through immunohistochemistry. The accuracy of hub genes as biomarkers for predicting SS was evaluated by receiver operating characteristic (ROC) curve. Results 834 DEGs were selected from the GSE157159 dataset, and a total of 39 pyroptosis-related DEGs were obtained. Functional analysis showed that these DEGs were significantly enriched in some inflammatory signaling pathways. Through the intersection of seven algorithms proposed by CytoHubba and validation using the GSE159574 dataset, 11 hub genes were identified, including IL18, AIM2, CCL5, CD274, GBP1, GBP5, GZMA, GZMB, TLR8, TNFS13B, and ICAM1. Finally, the results of immunohistochemistry showed that GSDMD, GZMA and GBP1 were all significantly highly expressed in SG from SS. And ROC analysis showed a high combined diagnostic value of the 3 genes (AUC=0.8858). Conclusion Our study revealed enhanced levels of pyroptosis in the SS. GZMA and GBP1 were identified as candidate genes for pyroptosis-induced inflammation of the SG in SS, which may be used as biomarkers or potential therapeutic targets for SS.

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Section: Discussionmentioning

confidence: 96%

Identification of Key Genes for Pyroptosis-Induced Salivary Gland Inflammation in Sjogren’s Syndrome Based on Microarray Data and Immunohistochemistry Analysis

Zhang,

Luo,

Zhu

et al. 2023

JIR

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“…As the most important endogenous nucleic acid sensitive TLR, TLR7 mediates transcription induction of type I IFN and other genes. If their activation is not controlled, it may lead to aseptic in ammation and autoimmunity [19]. In the current study, we examined TLR7 expression in LSGs from pSS patients.…”

Section: Discussionmentioning

confidence: 99%

Elevated expression of Toll-like receptor 7 and its correlation with clinical features in patients with primary Sjogren's syndrome

Yang,

Sun,

Wang

et al. 2023

Preprint

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Background The labial salivary glands (LSGs) are important for the diagnosis, evaluation of therapeutic efficacy, and genetic analyses of primary Sjogren's syndrome (pSS). In autoimmune diseases, the recognition of self nucleic acids and viral RNA and DNA through endogenous Toll-like receptor(TLR) triggers the production of type I IFN and pro-inflammatory cytokines, leading to the occurrence and progression of the disease. Here, we detected the expression of TLR7 in LSGs and analyse its correlation with clinical features and serum cytokines in pSS patients. Methods LSGs and serum samples were obtained from 56 pSS patients and 19 non-SS patients (non-pSS patients). The expression of TLR7 in the LSGs was evaluated with immunohistochemistry. The serum levels of interferon-α (IFN-α) and interleukin-6 (IL-6) were quantified by ELISA. Laboratory parameters were measured by clinical standard laboratory techniques. Results TLR7-positive cells in pSS were localized in the ductal epithelial cells and lymphocytes of LSGs. The expression of TLR7 was upregulated in pSS patients compared with controls. Patients with anti-Ro52 antibody positivity showed higher TLR7 levels than those who were negative but not those with anti-Ro60 and anti-SSB. TLR7 levels were positively associated with the levels of IgG, IgA, ANA, IL-6, IFN-α and serum globulin but were not associated with IgM, C3, C4, or rheumatoid factor (RF) in serum. Conclusion TLR7 may be involved in the inflammatory response and the production of antibodies in pSS and plays an important role in local and systemic pSS manifestations. This research showed that TLR7 is involved in pSS pathogenesis.

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“…Sjogren’s syndrome (SS) is also associated with TLR7 expression [ 62 , 63 ]. SS is a rheumatoid autoimmune disorder characterized by dry eyes and a dry mouth, and often accompanies lupus and rheumatoid arthritis.…”

Section: Tlr7 Implication In a Variety Of Clinical Diseasesmentioning

confidence: 99%

Recent Advances on Small-Molecule Antagonists Targeting TLR7

Zheng

Bonnet

2023

Molecules

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Toll-like receptor 7 (TLR7) is a class of pattern recognition receptors (PRRs) recognizing the pathogen-associated elements and damage and as such is a major player in the innate immune system. TLR7 triggers the release of pro-inflammatory cytokines or type-I interferons (IFN), which is essential for immunoregulation. Increasing reports also highlight that the abnormal activation of endosomal TLR7 is implicated in various immune-related diseases, carcinogenesis as well as the proliferation of human immunodeficiency virus (HIV). Hence, the design and development of potent and selective TLR7 antagonists based on small molecules or oligonucleotides may offer new tools for the prevention and management of such diseases. In this review, we offer an updated overview of the main structural features and therapeutic potential of small-molecule antagonists of TLR7. Various heterocyclic scaffolds targeting TLR7 binding sites are presented: pyrazoloquinoxaline, quinazoline, purine, imidazopyridine, pyridone, benzanilide, pyrazolopyrimidine/pyridine, benzoxazole, indazole, indole, and quinoline. Additionally, their structure-activity relationships (SAR) studies associated with biological activities and protein binding modes are introduced.

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Nucleic acid-sensing toll-like receptors: Important players in Sjögren’s syndrome

Cited by 7 publications

References 158 publications

Identification of Key Genes for Pyroptosis-Induced Salivary Gland Inflammation in Sjogren’s Syndrome Based on Microarray Data and Immunohistochemistry Analysis

Identification of Key Genes for Pyroptosis-Induced Salivary Gland Inflammation in Sjogren’s Syndrome Based on Microarray Data and Immunohistochemistry Analysis

Elevated expression of Toll-like receptor 7 and its correlation with clinical features in patients with primary Sjogren's syndrome

Recent Advances on Small-Molecule Antagonists Targeting TLR7

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