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Preclinical Evidence for the Glucocorticoid-Sparing Potential of a Dual Toll-Like Receptor 7/8 Inhibitor in Autoimmune Diseases

ABSTRACT: Single cell RNA-seq analysis of PBMCs testing for a synergistic effect of TLR7/8 inhibition and the glucocorticoid dexamethasone

ORGANISM(S): Homo sapiens

PROVIDER: GSE235927 | GEO | 2023/09/01

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE235927_steroid.synergy.post-bc.FINALforpublication.RDS.gz	Other
	GSE235927_steroid.synergy.post-bc.FINALforpublication.h5ad.gz	Other

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Preclinical Evidence for the Glucocorticoid-Sparing Potential of a Dual Toll-Like Receptor 7/8 Inhibitor in Autoimmune Diseases

Project description:Preclinical Evidence for the Glucocorticoid-Sparing Potential of a Dual Toll-Like Receptor 7/8 Inhibitor in Autoimmune Diseases

| PRJNA988047 | ENA

An endosomal toll-like receptor inhibitor drug with therapeutic effects in autoimmune diseases

Project description:Autoimmune disease is a systemic inflammatory response of immune blood cells caused by self-tolerance dysfunction, due to genetic or environmental factors or a combination thereof. Studies on autoimmune disease regarding the inhibition of toll-like receptor (TLR)7/9-MyD axis or the regulation of plasmacytoid dendritic cells (pDCs) and Th17 comprising an abundance of respective receptors have shown improvements in phenotypes or molecular markers, providing clues to the practicality of the inhibitors of endosomal TLRs. This study discovered several small-molecule compounds in endosomes exerting specific inhibitory effects on SITE1 shared among TLR 3, 7, 8, and 9, named endosomal TLR inhibitors (ETIs). The drug discovery process involved identifying lead compounds optimized to the receptors using a quantitative structure-activity relationship model and subsequent modification of the compounds to improve their binding affinity to target proteins. To propose a method of verifying the drug effects against side or placebo effect arising from false positives, the drug evaluation process converged from cellular response to signaling process to protein binding. Drug values on the inhibition of endosomal TLRs in autoimmune disease were assessed based on the onset of mild-to-life-threatening autoimmune disease including psoriasis, systemic lupus erythematosus, and multiple sclerosis. Complete healing was achieved for psoriasis through direct or indirect association with TLRs. Therapeutic potential of the novel ETIs for psoriasis was verified and is considered an effective drug for other autoimmune diseases associated with the TLR7/9-MyD axis.

2024-02-29 | GSE255890 | GEO

TNIP1 in Autoimmune Diseases: Regulation of Toll-like Receptor Signaling.

Project description: Not available

| S-EPMC6192141 | biostudies-other

Oncogenic MyD88 Mutants Require Toll-like Receptors

Project description:In the activated B-cell-like (ABC) subtype of diffuse large B cell lymphoma (DLBCL), the most frequent gain-of-function mutations target MyD88, a signaling adapter for Tolllike receptors (TLRs). The most prevalent oncogenic mutant, MyD88 L265P, occurs in 29% of cases and is the most active in engaging the NF-kappaB pathway. Here we show that MyD88 mutants do not function autonomously, but rather require TLR7, TLR9, and to a lesser extent, TLR4 to promote the survival of ABC DLBCL cells. Unlike wild type MyD88, MyD88 mutants associate constitutively with TLR7 and TLR9 in ABC DLBCL cells. Like ligand-induced TLR7/9 signaling in normal immune cells, the survival of ABC DLBCL cell lines depends upon translocation of TLR7 and TLR9 to acidic endolysosomes, where proteolytic processing of their ligand binding ectodomains is required for their oncogenic signaling. ABC DLBCL viability also depends upon CD14, a co-receptor for TLR7 and TLR9 that promotes engagement of nucleic acid ligands by these receptors. Point mutations in the TLR7 or TLR9 ectodomains that abrogate ligand binding and/or signaling were incapable of sustaining ABC DLBCL survival. An inhibitory oligonucleotide that suppresses TLR9 responses in normal B cells blocked NF-kappaB signaling and survival of ABC DLBCL lines. Together, these data suggest that an endogenous TLR ligand may play a pathogenic role in ABC DLBCL and provide a rationale for targeting TLR signaling to improve therapy of this aggressive lymphoma. Gene expression was analyzed using Agilent human 2-color 4X44K oligo gene expression arrays. Cell line, TMD8 ABC-DLBCL, was infected with control (shControl, Cy3), shLTR7 (Cy5) or shLTR9 (Cy5) and changes in gene expression were monitored on day 1 and day 2 after induction of the shRNA with doxycycline, co-hybridizing control and experimental samples (Cy3+Cy5), for a total of 4 arrays.

2014-05-21 | E-GEOD-47147 | biostudies-arrayexpress

Toll like receptor 2release by macrophages

Project description:THP-1 cells were cultured and EVCs were isolated after treatment with dexamethasone, LPS and a mixture of dexamethasone/LPS or non treated (control) by ultracentrifugation. Proteins were separated by 1D SDS-PAGE, tryptic digested and analyzed by nanoLC-MSMS

2019-08-13 | PXD013977 | Pride

HMGB1 and Toll-like receptors: potential therapeutic targets in autoimmune diseases.

Project description: Not available

| S-EPMC10478470 | biostudies-literature

Oncogenic MyD88 Mutants Require Toll-like Receptors

2014-05-21 | GSE47147 | GEO

Dual-Directional Immunomodulatory Effects of Corbrin Capsule on Autoimmune Thyroid Diseases.

Project description: Not available

| S-EPMC5045992 | biostudies-literature

Engineering Cell Therapies for Autoimmune Diseases: From Preclinical to Clinical Proof of Concept.

Project description: Not available

| S-EPMC9634148 | biostudies-literature

Toll-like receptor 7 is a primary sensor of malaria infection

Project description:Microarray profiling of amplified total splenic RNA isolated from TLR9-, TLR7-, UNC93b1- or MYD88- deficient mice or their C57BL/6 controls 24h after mock infection or infection with Plasmodium chabaudi. 4 independent replicates collected from each genotype/infection group, RNA isolated and amplified from whole spleen. Hybridized as a one color experiment.

2013-09-21 | E-GEOD-41496 | biostudies-arrayexpress

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