Retrotransposons in Werner syndrome-derived macrophages trigger type I interferon-dependent inflammation in an atherosclerosis model.
Sudip Kumar PaulMotohiko OshimaAshwini PatilMasamitsu SoneHisaya KatoYoshiro MaezawaHiyori KanekoMasaki FukuyoBahityar RahmutullaYasuo OuchiKyoko TsujimuraMahito NakanishiAtsushi KanedaAtsushi IwamaKoutaro YokoteKoji EtoNaoya TakayamaPublished in: Nature communications (2024)
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.
Keyphrases
- endothelial cells
- cell proliferation
- transcription factor
- ejection fraction
- vascular smooth muscle cells
- dendritic cells
- cardiovascular disease
- gene expression
- newly diagnosed
- dna damage
- prognostic factors
- genome wide
- induced pluripotent stem cells
- single cell
- case report
- patient reported outcomes
- minimally invasive
- drug delivery
- dna methylation
- cancer therapy
- heat stress