Identification of ALEKSIN as a novel multi-IRF inhibitor of IRF- and STAT-mediated transcription in vascular inflammation and atherosclerosis [HMEC]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1126115 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29470985.fastq.gz | Fastqsanger.gz | |||
| SRR29470986.fastq.gz | Fastqsanger.gz | |||
| SRR29470987.fastq.gz | Fastqsanger.gz | |||
| SRR29470988.fastq.gz | Fastqsanger.gz | |||
| SRR29470989.fastq.gz | Fastqsanger.gz |
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Project description:Cardiovascular diseases (CVDs) include atherosclerosis, which is an inflammatory disease of large and medium vessels that leads to atherosclerotic plaque formation. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of IFN Regulatory Factors (IRFs) as well as Signal Transducer and Activator of Transcription (STAT)s. Based on their promoting role in atherosclerosis, we hypothesized that combined inhibition of IRFs and STATs blocks pro-inflammatory target gene expression and may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple IRF-DBD models on a multi-million natural compound library, we identified the novel multi-IRF inhibitor, ALEKSIN. This compound targets the DBD domain of IRF1, IRF2, and IRF8 with the same affinity and simultaneously inhibits expression of multiple IRF-target genes in HMECs in response to IFNa and IFNg. Under the same conditions, ALEKSIN was also shown to inhibit phosphorylation of STATs, potentially through low-affinity STAT-SH2 binding, however with lower potency as the known multi-STAT inhibitor STATTIC. This was in line with the common inhibition of ALEKSIN and STATTIC observed on genome-wide expression of pro-inflammatory IRF/STAT/NF-κB target genes, as well as on migration of HMECs. Finally, we identified a novel signature of 46 ALEKSIN and STATTIC commonly inhibited pro-atherogenic target genes, that was upregulated in atherosclerotic plaques in aorta's of high-fat diet fed APOE-/- mice and associated with inflammation, proliferation, adhesion, chemotaxis and response to lipid. Together, this suggests that ALEKSIN represents a novel class of multi-IRF inhibitors, which inhibit IRF- , STAT- and NF-κB-mediated transcription and could offer great promise for the treatment of CVDs. Also, the ALEKSIN and STATTIC commonly inhibited pro-inflammatory gene signature could serve to monitor plaque progression during experimental atherosclerosis.
2025-01-02 | GSE270277 | GEO
Project description:Cardiovascular diseases (CVDs) include atherosclerosis, which is an inflammatory disease of large and medium vessels that leads to atherosclerotic plaque formation. Key factors contributing to onset and progression of atherosclerosis include the pro-inflammatory cytokines Interferon (IFN)α and IFNγ and the Pattern Recognition Receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger activation of IFN Regulatory Factors (IRFs) as well as Signal Transducer and Activator of Transcription (STAT)s. Based on their promoting role in atherosclerosis, we hypothesized that combined inhibition of IRFs and STATs blocks pro-inflammatory target gene expression and may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple IRF-DBD models on a multi-million natural compound library, we identified the novel multi-IRF inhibitor, ALEKSIN. This compound targets the DBD domain of IRF1, IRF2, and IRF8 with the same affinity and simultaneously inhibits expression of multiple IRF-target genes in HMECs in response to IFNa and IFNg. Under the same conditions, ALEKSIN was also shown to inhibit phosphorylation of STATs, potentially through low-affinity STAT-SH2 binding, however with lower potency as the known multi-STAT inhibitor STATTIC. This was in line with the common inhibition of ALEKSIN and STATTIC observed on genome-wide expression of pro-inflammatory IRF/STAT/NF-κB target genes, as well as on migration of HMECs. Finally, we identified a novel signature of 46 ALEKSIN and STATTIC commonly inhibited pro-atherogenic target genes, that was upregulated in atherosclerotic plaques in aorta's of high-fat diet fed APOE-/- mice and associated with inflammation, proliferation, adhesion, chemotaxis and response to lipid. Together, this suggests that ALEKSIN represents a novel class of multi-IRF inhibitors, which inhibit IRF- , STAT- and NF-κB-mediated transcription and could offer great promise for the treatment of CVDs. Also, the ALEKSIN and STATTIC commonly inhibited pro-inflammatory gene signature could serve to monitor plaque progression during experimental atherosclerosis.
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Project description:Identification of ALEKSIN as a novel multi-IRF inhibitor of IRF- and STAT-mediated transcription in vascular inflammation and atherosclerosis [ApoEKO]
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2020-01-21 | PXD017125 | Pride
Project description:Cardiovascular diseases (CVDs) include atherosclerosis, which is an inflammatory disease of large and medium vessels that leads to atherosclerotic plaque formation. The key factors contributing to the onset and progression of atherosclerosis include the pro-inflammatory cytokines interferon (IFN)α and IFNγ and the pattern recognition receptor (PRR) Toll-like receptor 4 (TLR4). Together, they trigger the activation of IFN regulatory factors (IRFs) and signal transducer and activator of transcription (STAT)s. Based on their promoting role in atherosclerosis, we hypothesized that the inhibition of pro-inflammatory target gene expression through multi-IRF inhibitors may be a promising strategy to treat CVDs. Using comparative in silico docking of multiple IRF-DNA-binding domain (DBD) models on a multi-million natural compound library, we identified the novel multi-IRF inhibitor, ALEKSIN. This compound targets the DBD of IRF1, IRF2, and IRF8 with the same affinity and simultaneously inhibits the expression of multiple IRF target genes in human microvascular endothelial cells (HMECs) in response to IIFNα and IFNγ. Under the same conditions, ALEKSIN also inhibited the phosphorylation of STATs, potentially through low-affinity STAT-SH2 binding but with lower potency than the known multi-STAT inhibitor STATTIC. This was in line with the common inhibition of ALEKSIN and STATTIC observed on the genome-wide expression of pro-inflammatory IRF/STAT/NF-κB target genes, as well as on the migration of HMECs. Finally, we identified a novel signature of 46 ALEKSIN and STATTIC commonly inhibited pro-atherogenic target genes, which was upregulated in atherosclerotic plaques in the aortas of high-fat diet-fed ApoEKO mice and associated with inflammation, proliferation, adhesion, chemotaxis, and response to lipids. Interestingly, the majority of these genes could be linked to macrophage subtypes present in aortic plaques in HFD-fed LDLR-KO mice. Together, this suggests that ALEKSIN represents a novel class of multi-IRF inhibitors, which inhibits IRF-, STAT-, and NF-κB-mediated transcription and could offer great promise for the treatment of CVDs. Furthermore, the ALEKSIN and STATTIC commonly inhibited pro-inflammatory gene signature could help monitor plaque progression during experimental atherosclerosis.
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Project description:Interferon Regulatory Factor-8, an Integral Determinant of Myeloid-Derived Suppressor Cell Subset Development. Myeloid-derived suppressor cells (MDSC) are a major barrier to anticancer responses. Although much is known about how MDSC promote tumor progression, little is known about how they develop. We hypothesized that MDSC develop as a consequence of tumor-induced downregulation of interferon regulatory factor-8 (IRF-8), a key myeloid developmental transcription factor. We showed that: 1) IRF8-deficiency in mice generated myeloid populations highly homologous to tumor-induced MDSC; 2) IRF-8 overexpression in mice reduced MDSC accumulation and retarded tumor growth; 3) MDSC-inducing factors, G-CSF or GM-CSF, facilitated IRF-8 downregulation via STAT3- or STAT5-dependent pathways, respectively; and 4) IRF-8 levels in MDSC-like subsets of breast cancer patients were depressed compared to healthy donors. Altogether, our data implicate IRF-8 as a novel MDSC-dependent transcription factor.
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