Epigenetic regulation of Toll-like receptors 2 and 4 in kidney disease

Shelke, Vishwadeep; Kale, Ajinath; Anders, Hans‐Joachim; Gaikwad, Anil Bhanudas

doi:10.1007/s00109-022-02218-y

Cited by 10 publications

(4 citation statements)

References 65 publications

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“…Another methylome cohort exhibited a tight correlation between methylation of TLR2 and overall survival (Fig. 5b ), which was consistent with the finding that abnormal methylated would influence the activation of neutrophils and lead to diseases 48 , 49 .…”

Section: Discussionsupporting

confidence: 86%

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer

Fu,

Tao,

et al. 2024

npj Precis. Onc.

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Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant neoplasm characterized by a poor prognosis and limited therapeutic strategy. The PDAC tumor microenvironment presents a complex heterogeneity, where neutrophils emerge as the predominant constituents of the innate immune cell population. Leveraging the power of single-cell RNA-seq, spatial RNA-seq, and multi-omics approaches, we included both published datasets and our in-house patient cohorts, elucidating the inherent heterogeneity in the formation of neutrophil extracellular traps (NETs) and revealed the correlation between NETs and immune suppression. Meanwhile, we constructed a multi-omics prognostic model that suggested the patients exhibiting downregulated expression of NETs may have an unfavorable outcome. We also confirmed TLR2 as a potent prognosis factor and patients with low TLR2 expression had more effective T cells and an overall survival extension for 6 months. Targeting TLR2 might be a promising strategy to reverse immunosuppression and control tumor progression for an improved prognosis.

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Section: Discussionsupporting

confidence: 86%

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer

Fu,

Tao,

et al. 2024

npj Precis. Onc.

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“…Indeed, stimulation with TLR2/4 agonists, which mimicked bacterial infection, increased the m6A level in DDX5-overexpressing cells but decreased it in DDX5 knockdown cells. An earlier study reported that TLR2 and TLR4 signaling was regulated through promoting the transcription of the TLR2 and TLR4 genes by different histone modifications of epigenetic regulation (Shelke et al, 2022 ). In addition, METTL3-mediated m6A mRNA methylation was found to regulate neutrophil activation by targeting TLR4 signaling pathway (Luo et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

DDX5 inhibits inflammation by modulating m6A levels of TLR2/4 transcripts during bacterial infection

Xu,

Liu,

Zhi

et al. 2024

EMBO Rep

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DExD/H-box helicases are crucial regulators of RNA metabolism and antiviral innate immune responses; however, their role in bacteria-induced inflammation remains unclear. Here, we report that DDX5 interacts with METTL3 and METTL14 to form an m6A writing complex, which adds N6-methyladenosine to transcripts of toll-like receptor (TLR) 2 and TLR4, promoting their decay via YTHDF2-mediated RNA degradation, resulting in reduced expression of TLR2/4. Upon bacterial infection, DDX5 is recruited to Hrd1 at the endoplasmic reticulum in an MyD88-dependent manner and is degraded by the ubiquitin-proteasome pathway. This process disrupts the DDX5 m6A writing complex and halts m6A modification as well as degradation of TLR2/4 mRNAs, thereby promoting the expression of TLR2 and TLR4 and downstream NF-κB activation. The role of DDX5 in regulating inflammation is also validated in vivo, as DDX5- and METTL3-KO mice exhibit enhanced expression of inflammatory cytokines. Our findings show that DDX5 acts as a molecular switch to regulate inflammation during bacterial infection and shed light on mechanisms of quiescent inflammation during homeostasis.

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“…TLR4 was shown abundantly expressed in all renal cell types, including renal tubular epithelial cells and podocytes ( 33 ). By promoting inflammation, programmed cell death, and endoplasmic reticulum stress, TLR4 has been linked to several acute and chronic renal disorders ( 34 ). Studies on contrast-induced AKI have found that contrast media increased the expression of TLR4 and up-regulate TLR4-related downstream inflammatory pathways ( 35 , 36 ).…”

Section: Discussionmentioning

confidence: 99%

Identification and validation of hub genes in drug induced acute kidney injury basing on integrated transcriptomic analysis

et al. 2023

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BackgroundDrug-induced acute kidney damage (DI-AKI) is a clinical phenomenon of rapid loss of kidney function over a brief period of time as a consequence of the using of medicines. The lack of a specialized treatment and the instability of traditional kidney injury markers to detect DI-AKI frequently result in the development of chronic kidney disease. Thus, it is crucial to continue screening for DI-AKI hub genes and specific biomarkers.MethodsDifferentially expressed genes (DEGs) of group iohexol, cisplatin, and vancomycin’s were analyzed using Limma package, and the intersection was calculated. DEGs were then put into String database to create a network of protein-protein interactions (PPI). Ten algorithms are used in the Cytohubba plugin to find the common hub genes. Three DI-AKI models’ hub gene expression was verified in vivo and in vitro using PCR and western blot. To investigate the hub gene’s potential as a biomarker, protein levels of mouse serum and urine were measured by ELISA kits. The UUO, IRI and aristolochic acid I-induced nephrotoxicity (AAN) datasets in the GEO database were utilized for external data verification by WGCNA and Limma package. Finally, the Elisa kit was used to identify DI-AKI patient samples.Results95 up-regulated common DEGs and 32 down-regulated common DEGs were obtained using Limma package. A PPI network with 84 nodes and 24 edges was built with confidence >0.4. Four hub genes were obtained by Algorithms of Cytohubba plugin, including TLR4, AOC3, IRF4 and TNFAIP6. Then, we discovered that the protein and mRNA levels of four hub genes were significantly changed in the DI-AKI model in vivo and in vitro. External data validation revealed that only the AAN model, which also belonged to DI-AKI model, had significant difference in these hub genes, whereas IRI and UUO did not. Finally, we found that plasma TLR4 levels were higher in patients with DI-AKI, especially in vancomycin-induced AKI.ConclusionThe immune system and inflammation are key factors in DI-AKI. We discovered the immunological and inflammatory-related genes TLR4, AOC3, IRF4, and TNFAIP6, which may be promising specific biomarkers and essential hub genes for the prevention and identification of DI-AKI.

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Epigenetic regulation of Toll-like receptors 2 and 4 in kidney disease

Cited by 10 publications

References 65 publications

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer

Multiomics integration reveals NETosis heterogeneity and TLR2 as a prognostic biomarker in pancreatic cancer

DDX5 inhibits inflammation by modulating m6A levels of TLR2/4 transcripts during bacterial infection

Identification and validation of hub genes in drug induced acute kidney injury basing on integrated transcriptomic analysis

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