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

Nat Commun. 2024 Jun 10;15(1):4772. doi: 10.1038/s41467-024-48663-w.

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.

MeSH terms

  • Atherosclerosis* / genetics
  • Atherosclerosis* / immunology
  • Atherosclerosis* / metabolism
  • Atherosclerosis* / pathology
  • Cell Proliferation
  • Cellular Senescence
  • Coculture Techniques
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism
  • Endothelial Cells / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Inflammation* / genetics
  • Inflammation* / metabolism
  • Inflammation* / pathology
  • Interferon Type I* / metabolism
  • Macrophages* / immunology
  • Macrophages* / metabolism
  • Muscle, Smooth, Vascular / metabolism
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / metabolism
  • Retroelements* / genetics
  • Signal Transduction
  • Werner Syndrome* / genetics
  • Werner Syndrome* / metabolism

Substances

  • Interferon Type I
  • Retroelements
  • DEAD-box RNA Helicases