TLR9: A friend or a foe

Saber, Mona M.; Monir, Nada; Awad, Azza S.; Elsherbiny, Marwa E.; Zaki, Hala F.

doi:10.1016/j.lfs.2022.120874

Cited by 15 publications

(8 citation statements)

References 111 publications

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“…However, the role of mucosal immunophysiology and gut microbiota in generating these protective IL-10-producing Bregs was unclear. Given B cells, which have high TLR9 expression ( 40 – 42 ), are one of the major mucosal immune cells and gut microbiota’s potential pathogenic role in T1D ( 16 , 43 – 45 ), we hypothesized that gut microbiota induce IL-10 elevation in B cell-specific TLR9-deficient NOD mice. To test this, we sequenced Tlr9 fl/fl Cd19 -Cre + NOD mice’s gut microbiota, revealing dominant mucin-degrading Lachnospiraceae bacteria.…”

Section: Discussionmentioning

confidence: 99%

Gut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10+ Breg cells and protect against T1D

Yang,

Huang,

Peng

et al. 2024

Front. Immunol.

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IntroductionType 1 diabetes (T1D) is an autoimmune disease characterized by the destruction of insulin-producing β cells. Toll-like receptor 9 (TLR9) plays a role in autoimmune diseases, and B cell-specific TLR9 deficiency delays T1D development. Gut microbiota are implicated in T1D, although the relationship is complex. However, the impact of B cell-specific deficiency of TLR9 on intestinal microbiota and the impact of altered intestinal microbiota on the development of T1D are unclear.ObjectivesThis study investigated how gut microbiota and the intestinal barrier contribute to T1D development in B cell-specific TLR9-deficient NOD mice. Additionally, this study explored the role of microbiota in immune regulation and T1D onset.MethodsThe study assessed gut permeability, gene expression related to gut barrier integrity, and gut microbiota composition. Antibiotics depleted gut microbiota, and fecal samples were transferred to germ-free mice. The study also examined IL-10 production, Breg cell differentiation, and their impact on T1D development.ResultsB cell-specific TLR9-deficient NOD mice exhibited increased gut permeability and downregulated gut barrier-related gene expression. Antibiotics restored gut permeability, suggesting microbiota influence. Altered microbiota were enriched in Lachnospiraceae, known for mucin degradation. Transferring this microbiota to germ-free mice increased gut permeability and promoted IL-10-expressing Breg cells. Rag-/- mice transplanted with fecal samples from Tlr9fl/flCd19-Cre+ mice showed delayed diabetes onset, indicating microbiota’s impact.ConclusionB cell-specific TLR9 deficiency alters gut microbiota, increasing gut permeability and promoting IL-10-expressing Breg cells, which delay T1D. This study uncovers a link between TLR9, gut microbiota, and immune regulation in T1D, with implications for microbiota-targeted T1D therapies.

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Section: Discussionmentioning

confidence: 99%

Gut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10+ Breg cells and protect against T1D

Yang,

Huang,

Peng

et al. 2024

Front. Immunol.

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“…Moreover, NFKB1 −/− bone marrow-derived macrophages show an increased expression of interferon-inducible genes, including IFN-β, in response to TLR-4 and TLR-9 stimulation [ 52 ]. Toll-like receptor 9 (TLR9) is an intracellular TLR, expressed in different immunological and non-immunological cells [ 53 ]. The gut microbiota is a source of TLR ligands, including TLR9.…”

Section: Discussionmentioning

confidence: 99%

The correlation between primary open-angle glaucoma (POAG) and gut microbiota: a pilot study towards predictive, preventive, and personalized medicine

et al. 2023

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Background Glaucoma is the leading cause of irreversible blindness worldwide. Emerged evidence has shown that glaucoma is considered an immune system related disorder. The gut is the largest immune organ in the human body and the gut microbiota (GM) plays an irreversible role in maintaining immune homeostasis. But, how the GM influences glaucoma remains unrevealed. This study aimed at investigating the key molecules/pathways mediating the GM and the glaucoma to provide new biomarkers for future predictive, preventive, and personalized medicine. Methods Datasets from the primary open-angle glaucoma (POAG) patients (GSE138125) and datasets for target genes of GM/GM metabolites were downloaded from a public database. For GSE138125, the differentially expressed genes (DEGs) between healthy and POAG samples were identified. And the online Venn diagram tool was used to obtain the DEGs from POAG related to GM. After which GM-related DEGs were analyzed by correlation analysis, pathway enrichment analysis, and protein–protein interaction (PPI) network analysis. Human trabecular meshwork cells were used for validation, and the mRNA level of hub genes was verified by quantitative real-time polymerase chain reaction (RT-qPCR) in the in vitro glaucoma model. Results A total of 16 GM-related DEGs in POAG were identified from the above 2 datasets (9 upregulated genes and 7 downregulated genes). Pathway enrichment analysis indicated that these genes are mostly enriched in immune regulation especially macrophages-related pathways. Then 6 hub genes were identified by PPI network analysis and construction of key modules. Finally, RT-qPCR confirmed that the expression of the hub genes in the in vitro glaucoma model was consistent with the results of bioinformatics analysis of the mRNA chip. Conclusion This bioinformatic study elucidates NFKB1, IL18, KITLG, TLR9, FKBP2, and HDAC4 as hub genes for POAG and GM regulation. Immune response modulated by macrophages plays an important role in POAG and may be potential targets for future predictive, preventive, and personalized diagnosis and treatment.

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“…TLR9 is a PRR that recognizes unmethylated cytidine-phosphate-guanosine (CpG) oligodeoxynucleotides derived from pathogens and responds to cellular components including proteins, nucleotides, and DNA, conferring protection against infections and maintaining homeostasis by removing cellular debris during physiological conditions. Uncontrolled or aberrant TLR9 signaling favors the development of inflammatory and autoimmune diseases during pathological cellular damage and stress signals ( 47 ). It was shown that Smurf1 is required for the negative regulation of TLR9-mediated inflammatory responses ( Figure 3 ).…”

Section: Regulation Of Innate Immune Signaling and Inflammation By Sm...mentioning

confidence: 99%

Uncovering new insights into the role of the ubiquitin ligase Smurf1 on the regulation of innate immune signaling and resistance to infection

Souza-Costa,

Andrade-Chaves,

Andrade

et al. 2023

Front. Immunol.

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Innate immunity is the body’s first line of defense against infections. Innate immune cells express pattern recognition receptors in distinct cellular compartments that are responsible to detect either pathogens-associated molecules or cellular components derived from damaged cells, to trigger intracellular signaling pathways that lead to the activation of inflammatory responses. Inflammation is essential to coordinate immune cell recruitment, pathogen elimination and to keep normal tissue homeostasis. However, uncontrolled, misplaced or aberrant inflammatory responses could lead to tissue damage and drive chronic inflammatory diseases and autoimmunity. In this context, molecular mechanisms that tightly regulate the expression of molecules required for the signaling of innate immune receptors are crucial to prevent pathological immune responses. In this review, we discuss the ubiquitination process and its importance in the regulation of innate immune signaling and inflammation. Then, we summarize the roles of Smurf1, a protein that works on ubiquitination, on the regulation of innate immune signaling and antimicrobial mechanisms, emphasizing its substrates and highlighting its potential as a therapeutic target for infectious and inflammatory conditions.

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TLR9: A friend or a foe

Cited by 15 publications

References 111 publications

Gut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10+ Breg cells and protect against T1D

Gut microbiota from B-cell-specific TLR9-deficient NOD mice promote IL-10+ Breg cells and protect against T1D

The correlation between primary open-angle glaucoma (POAG) and gut microbiota: a pilot study towards predictive, preventive, and personalized medicine

Uncovering new insights into the role of the ubiquitin ligase Smurf1 on the regulation of innate immune signaling and resistance to infection

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