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Identification of ALEKSIN as a novel multi-IRF inhibitor of IRF- and STAT-mediated transcription in vascular inflammation and atherosclerosis [ApoEKO]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE270260 | GEO | 2025/01/02

REPOSITORIES: GEO

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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.

Project description:We investigated the roles of IRF-3 and IRF-7 in innate antiviral immunity against dengue virus (DENV). Double-deficient Irf-3-/-7-/- mice infected with the DENV2 strain S221 possessed 1,000-150,000 fold higher levels of viral RNA than wild-type and single-deficient mice 24 hours after infection; however, they remained resistant to lethal infection. IFN-α/β was induced similarly in wild-type and Irf-3-/- mice post DENV infection, whereas in the Irf-7-/- and Irf-3-/-7-/- mice, significantly low levels of IFN-α/β expression was observed within 24 hours post-infection. IFN-stimulated gene (ISG) induction was also delayed in Irf-3-/-7-/- mice relative to wild-type and single-deficient mice. In particular, Cxcl10 and Ifnα2 were rapidly induced independently of both IRF-3 and IRF-7 in the Irf-3-/-7-/- mice with DENV infection. Higher levels of serum IFN-γ, IL-6, CXCL10, IL-8, IL-12 p70, and TNF were also observed in Irf-3-/-7-/- mice 24 hours after infection, at which time point viral titers peaked and started to be cleared. Antibody-mediated blockade experiments revealed that IFN-γ, CXCL10, and CXCR3 function to restrict DENV replication in Irf-3-/-7-/- mice. Additionally, the ISGs Cxcl10, Ifit1, Ifit3, and Mx2 can be induced via an IRF-3- and IRF-7-independent pathway that does not involve IFN-γ signaling for protection against DENV. Collectively, these results demonstrate that IRF-3 and IRF-7 are redundant, albeit IRF-7 plays a more important role than IRF-3 in inducing the initial IFN-α/β response; only the combined actions of IRF-3 and IRF-7 are necessary for efficient control of early DENV infection; and the late, IRF-3- and IRF-7-independent pathway contributes to anti-DENV immunity. To identify the antiviral genes that are controlled by IRF-3 and IRF-7 signaling during DENV infection, we examined a panel of ISG expression in the spleens of wild-type, Irf-3-/-, Irf-7-/- and Irf-3-/-7-/- mice at 12 or 24 hours after DENV infection using a quantitative PCR array kit. The fold changes in expression of 55 genes from infected mice were normalized to that of strain-matched naïve mice.

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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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