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

Abstract The underlying mechanisms of the second leading cause of death among Werner syndrome (WS) patients, atherosclerosis, 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. WS-iMφs induced endothelial dysfunction and characteristics of phenotype switching in WS-iVECs and WS-iVSMCs, respectively. 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, we found higher expression of retrotransposable elements in WS-iMφs and WS peripheral blood-derived-Mφs and evidence that retrotransposable element-derived dsRNA may activate the DHX58-dependent cytoplasmic RNA sensing pathway in WS-iMφs. Conversely, silencing type I interferon signaling in WS-iMφs 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.