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Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model [RTE RNA-seq]

ABSTRACT: The underlying mechanisms of atherosclerosis, the second leading cause of death among Werner syndrome (WS) patients, is not fully understood. Here, we established an in vitro co-culture system using macrophages (iMφs), vascular endothelial cells (iVECs), and vascular smooth muscle cells (iVSMCs) derived from induced pluripotent stem cells. In co-culture, WS-iMφs induced endothelial dysfunction in WS-iVECs and characteristics of the synthetic phenotype in WS-iVSMCs. RNA-seq and ATAC-seq revealed accelerated activation of type I interferon signaling and reduced chromatin accessibility of several transcriptional binding sites required for cellular homeostasis in WS-iMφs. Furthermore, the reduced H3K9me3 levels showed inverse correlation with retrotransposable elements, and retrotransposable element-derived dsRNA activated the DHX58-dependent cytoplasmic RNA sensing pathway in WS-iMφs. Conversely, silencing type I interferon signaling in WS-iMφs rescued cell proliferation and suppressed cellular senescence and inflammation. These findings suggest that Mφ-specific inhibition of type I interferon signaling could be targeted to treat atherosclerosis in WS patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE247721 | GEO | 2024/03/20

REPOSITORIES: GEO

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Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model [iPS-VEC RNA-seq]

Project description:The underlying mechanisms of atherosclerosis, the second leading cause of death among Werner syndrome (WS) patients, is not fully understood. Here, we established an in vitro co-culture system using macrophages (iMφs), vascular endothelial cells (iVECs), and vascular smooth muscle cells (iVSMCs) derived from induced pluripotent stem cells. In co-culture, WS-iMφs induced endothelial dysfunction in WS-iVECs and characteristics of the synthetic phenotype in WS-iVSMCs. RNA-seq and ATAC-seq revealed accelerated activation of type I interferon signaling and reduced chromatin accessibility of several transcriptional binding sites required for cellular homeostasis in WS-iMφs. Furthermore, the reduced H3K9me3 levels showed inverse correlation with retrotransposable elements, and retrotransposable element-derived dsRNA activated the DHX58-dependent cytoplasmic RNA sensing pathway in WS-iMφs. Conversely, silencing type I interferon signaling in WS-iMφs rescued cell proliferation and suppressed cellular senescence and inflammation. These findings suggest that Mφ-specific inhibition of type I interferon signaling could be targeted to treat atherosclerosis in WS patients.

2024-03-20 | GSE247710 | GEO

Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model [H3K9me3 ChIP-seq]

2024-03-20 | GSE247705 | GEO

Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model [VSMC RNA-seq]

2024-03-20 | GSE247718 | GEO

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2024-03-20 | GSE247716 | GEO

Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model

Project description:The underlying mechanisms of atherosclerosis, the second leading cause of death among Werner syndrome (WS) patients, are not fully understood. Here, we establish an in vitro co-culture system using macrophages (iMφs), vascular endothelial cells (iVECs), and vascular smooth muscle cells (iVSMCs) derived from induced pluripotent stem cells. In co-culture, WS-iMφs induces endothelial dysfunction in WS-iVECs and characteristics of the synthetic phenotype in WS-iVSMCs. Transcriptomics and open chromatin analysis reveal accelerated activation of type I interferon signaling and reduced chromatin accessibility of several transcriptional binding sites required for cellular homeostasis in WS-iMφs. Furthermore, the H3K9me3 levels show an inverse correlation with retrotransposable elements, and retrotransposable element-derived double-stranded RNA activates the DExH-box helicase 58 (DHX58)-dependent cytoplasmic RNA sensing pathway in WS-iMφs. Conversely, silencing type I interferon signaling in WS-iMφs rescues cell proliferation and suppresses cellular senescence and inflammation. These findings suggest that Mφ-specific inhibition of type I interferon signaling could be targeted to treat atherosclerosis in WS patients.

2024-03-20 | GSE247722 | GEO

Pre-treatment of Interferon-α stimulates DHX58 to prevent hepatic ferroptosis

Project description:Characterized by lethal iron accumulation and lipid peroxidation, ferroptosis plays critical roles in liver injury, especially caused by ischemia/reperfusion (I/R) of hepatic inflow occlusion during liver operation. However, the lack of effective and safe clinical precautionary measure is still the main problem in preventing hepatic ferroptosis. Here, we found that the excessive production of reactive oxygen species could decrease the expression of Interferon (IFN)-stimulated gene DExH-box helicase 58 (DHX58) in hepatocytes, and then promote hepatic ferroptosis, while pre-treatment using IFN-α increased DHX58 expression and prevented ferroptosis during I/R injury. Mechanistically, DHX58 with RNA-binding activity could constitutively associate the mRNA of glutathione peroxidase 4 (GPX4), a crucial ferroptosis suppressor, and then recruit the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in m6A-dependent manner, thus enhancing GPX4 protein level and preventing hepatic ferroptosis. Therefore, we provide mechanistic evidence for the IFN-stimulated DHX58 in promoting the translation of m6A-modified Gpx4 mRNA, and suggest the promising clinical potential of IFN-α pre-treatment in the prevention of hepatic ferroptosis.

2024-05-24 | PXD042083 | Pride

Ligustilide targets SMAD3, obstructing vascular fibrosis process in preventing atherosclerosis

Project description:Atherosclerosis is a persistent inflammatory state accompanied by lipid overload. Vascular fibrosis is one of the primary causes of atherosclerosis development. Although ligustilide (Lig) was shown to exert obvious antiatherogenic effects in previous studies, its precise mechanism has not been comprehensively discussed. In this paper, pharmacologic studies were performed to explore the pharmacodynamic effects of Lig on protecting aorta vascular wall structures and modulating serum inflammatory factors in ApoE-/- mice. Chemical proteomics based on a Lig-derived photoaffinity labelling (Lig-PAL) probe were applied to identify potential therapeutic targets. Mothers against decapentaplegic homologue 3 (SMAD3), which is closely related to the development of vascular fibrosis and atherosclerosis, was identified as a potential target of Lig. Lig suppressed the phosphorylation and nuclear translocation of SMAD3 by blocking the interaction between SMAD3 and transforming growth factor-β (TGF-β) receptor 1, thereby inhibiting the collagen synthesis process, preventing vascular fibrosis and improving atherosclerosis. The quantitative proteomics results from Lig-treated atherosclerotic ApoE-/- mice also indicated that Lig inhibits the expression of collagens I and III, interferes with collagen fibril organization processes and protects the aorta from vascular fibrosis. Hence, developing a novel SMAD3 inhibitor may present another therapeutic option for preventing atherosclerosis.

2020-01-21 | PXD017125 | Pride

Efficient direct reprogramming of c-Kit− mature amniotic cells into endothelial cells by ETS factors and TGFβ suppression

Project description:ETS transcription factors ETV2, FLI1 and ERG1 specify pluripotent stem cells into endothelial cells (PSC-ECs). However, these PSC-ECs are unstable and often drift towards non-vascular cell fates. We show that human mid-gestation c-Kit- lineage-committed amniotic cells (ACs) can be reprogrammed into induced vascular endothelial cells (rAC-VECs). Transient ETV2 expression in ACs generated immature iVECs, while co-expression with FLI1/ERG1 endowed rAC-VECs with a vascular repertoire and morphology matching mature ECs. Brief TGFb-inhibition functionalizes VEGFR2 signaling, augmenting specification of ACs into rAC-VECs. Genome-wide transcriptional analyses showed that rAC-VECs are similar to adult ECs in which vascular-specific genes are expressed and non-vascular genes are silenced. Functionally, rAC-VECs form stable vasculature in Matrigel plugs and regenerating livers. Thus, short-term ETV2 expression and TGFb-inhibition along with constitutive ERG1/FLI1 co-expression reprogram mature ACs into generic rAC-VECs with clinical-scale expansion potential. Public banking of HLA-typed rAC-VECs would establish a vascular inventory for treatment of genetically diverse disorders. Transcriptome sequencing of clonal and non-clonal rAC-VECs, HUVECs, LSECs, CD34+/Lin-, BMS

2012-10-30 | E-GEOD-40291 | biostudies-arrayexpress

Expression data from human healthy CD133+ bone marrow EPCs

Project description:Systemic lupus erythematosus (SLE) is characterized by increased vascular risk due to premature atherosclerosis independent of traditional risk factors. We previously proposed that interferon-α plays a crucial role in premature vascular damage in SLE. IFN-α alters the balance between endothelial cell apoptosis and vascular repair mediated by endothelial progenitor cells (EPCs) and myeloid circulating angiogenic cells (CACs). Here we demonstrate that IFN-α promotes an antiangiogenic signature in SLE and control EPCs/CACs, characterized by transcriptional repression of IL-1α and β, IL-1 receptor 1 and vascular endothelial growth factor A (VEGF-A) and upregulation of IL-1 receptor antagonist (IL-1RN) and the decoy receptor IL1-R2. IL-1β promotes significant improvement in the functional capacity of lupus EPCs/CACs, therefore abrogating the deleterious effects of IFN-α. We used microarrays to analyze the effect of IFNα on peripheral blood EPCs/CACs and on bone marrow EPCs exposed to proangiogenic stimulation. Human healthy EPCs from bone marrow were isolated and cultured under proangiogenic stimulation; after IFNa incubation or not, RNA was extracted and processed for hybridization on Affymetrix microarrays.

2011-04-13 | E-GEOD-26951 | biostudies-arrayexpress

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