Preclinical Evidence for the Glucocorticoid-Sparing Potential of a Dual Toll-Like Receptor 7/8 Inhibitor in Autoimmune Diseases
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE235927 | GEO | 2023/09/01
REPOSITORIES: GEO
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Project description:Preclinical Evidence for the Glucocorticoid-Sparing Potential of a Dual Toll-Like Receptor 7/8 Inhibitor in Autoimmune Diseases
| PRJNA988047 | ENA
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
Project description:TNIP1 protein is increasingly being recognized as a key repressor of inflammatory signaling and a potential factor in multiple autoimmune diseases. In addition to earlier foundational reports of TNIP1 SNPs in human autoimmune diseases and TNIP1 protein-protein interaction with receptor regulating proteins, more recent studies have identified new potential interaction partners and signaling pathways likely modulated by TNIP1. Subdomains within the TNIP1 protein as well as how they interact with ubiquitin have not only been mapped but inflammatory cell- and tissue-specific consequences subsequent to their defective function are being recognized and related to human disease states such as lupus, scleroderma, and psoriasis. In this review, we emphasize receptor signaling complexes and regulation of cytoplasmic signaling steps downstream of TLR given their association with some of the same autoimmune diseases where TNIP1 has been implicated. TNIP1 dysfunction or deficiency may predispose healthy cells to the inflammatory response to otherwise innocuous TLR ligand exposure. The recognition of the anti-inflammatory roles of TNIP1 and improved integrated understanding of its physical and functional association with other signaling pathway proteins may position TNIP1 as a candidate target for the design and/or testing of next-generation anti-inflammatory therapeutics.
| S-EPMC6192141 | biostudies-other
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
Project description:HMGB1, a nucleoprotein, is expressed in almost all eukaryotic cells. During cell activation and cell death, HMGB1 can function as an alarm protein (alarmin) or damage-associated molecular pattern (DAMP) and mediate early inflammatory and immune response when it is translocated to the extracellular space. The binding of extracellular HMGB1 to Toll-like receptors (TLRs), such as TLR2 and TLR4 transforms HMGB1 into a pro-inflammatory cytokine, contributing to the occurrence and development of autoimmune diseases. TLRs, which are members of a family of pattern recognition receptors, can bind to endogenous DAMPs and activate the innate immune response. Additionally, TLRs are key signaling molecules mediating the immune response and play a critical role in the host defense against pathogens and the maintenance of immune balance. HMGB1 and TLRs are reported to be upregulated in several autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, and autoimmune thyroid disease. The expression levels of HMGB1 and some TLRs are upregulated in tissues of patients with autoimmune diseases and animal models of autoimmune diseases. The suppression of HMGB1 and TLRs inhibits the progression of inflammation in animal models. Thus, HMGB1 and TLRs are indispensable biomarkers and important therapeutic targets for autoimmune diseases. This review provides comprehensive strategies for treating or preventing autoimmune diseases discovered in recent years.
| S-EPMC10478470 | biostudies-literature
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.
2014-05-21 | GSE47147 | GEO
Project description:Purpose. To investigate the effects of Corbrin Capsule (CS-C-Q80), a drug derived from Cordyceps sinensis (Berk.) Sacc., on autoimmune thyroid diseases (AITD). Methods. 44 Patients with Graves's disease (GD) and 56 patients with Hashimoto's thyroiditis (HT) were randomly assigned to treatment group (GD-Tx and HT-Tx) or control group (GD-Ct and HT-Ct). The control groups were given methimazole or levothyroxine only while the treatment groups were given Corbrin Capsule (2.0 g tid) besides the same conventional prescriptions as control groups. Thyroid hormones, thyroid antibodies, and T lymphocyte subsets were quantified at baseline and 24 weeks posttreatment. Results. Significant drop of serum anti-TPO-Ab levels was observed in both GD-Tx and HT-Tx groups. Before treatment, GD patients had higher helper T cells compared to cytotoxic T cells, while HT patients suffered from a nearly inverted proportion of helper T/cytotoxic T cells. There was a significant drop of the helper T/cytotoxic T cells ratio in GD-Tx to the median of the normal ranges after Corbrin treatment for 24 weeks, while that in HT-Tx was elevated. Conclusion. Corbrin Capsule could restore the balance between helper T and cytotoxic T cells in both GD and HT patients with dual-directional immunomodulatory effects. And it could significantly reduce the autoantibody levels in both GD and HT.
| S-EPMC5045992 | biostudies-literature
Project description:LC-MS data and DIA-NN search files relating to: PU.1 Eviction at Lymphocyte-Specific Chromatin Domains Mediates Glucocorticoid Response in Acute Lymphoblastic Leukemia.
Abstract: The epigenetic landscape plays a critical role in the onset and evolution of various malignancies, but its therapeutic utility remains underutilized. Glucocorticoids are an essential part of many multi-agent treatment regimens for lymphoid malignancies. However, the emergence of glucocorticoid resistance is a significant barrier to cure, which is in part due to epigenetic alterations, including aberrant chromatin accessibility and hypermethylation at lymphocyte-specific glucocorticoid-response elements (GREs). To gain a deeper understanding of regulatory mechanisms leading to these epigenetic alterations, we conducted a multi-omics study, including chromosome conformation capture sequencing (HiC), to examine changes in the 3D genome structure following the in vivo treatment of acute lymphoblastic leukemia (ALL) patient-derived xenografts (PDXs) with glucocorticoid. We found that glucocorticoid treatment led to distinct patterns of topologically associated domains (TADs) in glucocorticoid sensitive compared to resistant PDXs. Furthermore, we show that these TADs were primed by the development-related pioneer transcription factor PU.1, which extensively interacts with the glucocorticoid receptor (GR) exclusively in glucocorticoid-sensitive ALL PDXs. An integrative analysis of rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) and ChIP-seq revealed that PU.1 binding was associated with lymphocyte-specific activation of GREs and GRE-interacting super-enhancers. The PU.1-associated TADs modulated epigenetic marks, and particularly the eviction of PU.1 promoted GR binding and the expression of signature genes, including BIM, ZBTB16 and RASA1, mediating glucocorticoid-induced apoptosis in ALL. These findings were phenocopied using a PU.1 inhibitor DB2313 to restore glucocorticoid sensitivity in ALL. Taken together, this study identified a new epigenetic pathway integrating PU.1 priming and PU.1-GR interaction which ultimately leads to PU.1 eviction in ALL. This pathway provides the first link between the activity of a lineage-specific transcription factor and epigenetic modulators mediating the response to glucocorticoids and thus offers a new avenue to translate fundamental epigenetic research into the clinic.
2024-10-03 | MSV000096019 | MassIVE
Project description:Autoimmune diseases are caused by a dysfunction of the acquired immune system. In a subset of autoimmune diseases, B cells escaping immune tolerance present autoantigen and produce cytokines and/or autoantibodies, resulting in systemic or organ-specific autoimmunity. Therefore, B cell depletion with monoclonal Abs targeting B cell lineage markers is standard care therapy for several B cell-mediated autoimmune disorders. In the last 5 years, genetically-engineered cellular immunotherapies targeting B cells have shown superior efficacy and long-term remission of B cell malignancies compared to historical clinical outcomes using B cell depletion with monoclonal Ab therapies. This has raised interest in understanding whether similar durable remission could be achieved with use of genetically-engineered cell therapies for autoimmunity. This review will focus on current human clinical trials using engineered cell therapies for B cell-associated autoimmune diseases.
| S-EPMC9634148 | biostudies-literature
Project description:Glucocorticoids are universally used in the treatment of acute lymphoblastic leukemia (ALL), and glucocorticoid resistance in leukemia cells confers a poor prognosis. To elucidate mechanisms of glucocorticoid resistance, we determined the prednisolone sensitivity of primary leukemia cells from 444 newly diagnosed ALL patients and found significantly higher expression of caspase 1 (CASP1) and its activator NLRP3 in glucocorticoid resistant leukemia cells, due to significantly lower somatic methylation of CASP1 and NLRP3 promoters. Over-expression of CASP1 resulted in cleavage of the glucocorticoid receptor, diminished glucocorticoid-induced transcriptional response and increased glucocorticoid resistance. Knockdown or inhibition of CASP1 significantly increased glucocorticoid receptor levels and mitigated glucocorticoid resistance in CASP1 overexpressing ALL. Our findings establish a new mechanism by which the NLRP3/CASP1 inflammasome modulates cellular levels of the glucocorticoid receptor and diminishes cell sensitivity to glucocorticoids. The broad impact on glucocorticoid transcriptional response suggests this mechanism could also modify glucocorticoid effects in other diseases.
2015-03-24 | GSE67044 | GEO