Back to Search
Start Over
Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model.
- Source :
-
Nature communications [Nat Commun] 2024 Jun 10; Vol. 15 (1), pp. 4772. Date of Electronic Publication: 2024 Jun 10. - Publication Year :
- 2024
-
Abstract
- 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.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Induced Pluripotent Stem Cells metabolism
Signal Transduction
Coculture Techniques
Myocytes, Smooth Muscle metabolism
Endothelial Cells metabolism
Muscle, Smooth, Vascular metabolism
Muscle, Smooth, Vascular pathology
DEAD-box RNA Helicases metabolism
DEAD-box RNA Helicases genetics
Cellular Senescence
Cell Proliferation
Interferon Type I metabolism
Werner Syndrome genetics
Werner Syndrome metabolism
Atherosclerosis metabolism
Atherosclerosis immunology
Atherosclerosis genetics
Atherosclerosis pathology
Macrophages metabolism
Macrophages immunology
Retroelements genetics
Inflammation metabolism
Inflammation pathology
Inflammation genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 15
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 38858384
- Full Text :
- https://doi.org/10.1038/s41467-024-48663-w