Monocyte-released HERV-K dUTPase engages TLR4 and MCAM causing endothelial mesenchymal transition

• Published in: JCI insight 2021-08, Vol.6 (15)
• Main Authors: Otsuki, Shoichiro, Saito, Toshie, Taylor, Shalina, Li, Dan, Moonen, Jan-Renier, Marciano, David P, Harper, Rebecca L, Cao, Aiqin, Wang, Lingli, Ariza, Maria E, Rabinovitch, Marlene
• Format: Article
• Language: English
• Subjects: Animals; CD146 Antigen - metabolism; Endogenous Retroviruses - metabolism; Endogenous Retroviruses - pathogenicity; Endothelial Cells - metabolism; Epithelial-Mesenchymal Transition - immunology; Hypertension, Pulmonary - immunology; Hypertension, Pulmonary - metabolism; Hypertension, Pulmonary - virology; Inflammation; Inflammation - metabolism; Inflammation - virology; Macrophages - immunology; Mice; Monocytes - immunology; Pulmonary Artery - immunology; Pulmonary Artery - pathology; Pyrophosphatases - metabolism; Signal Transduction; Snail Family Transcription Factors - metabolism; Vascular biology
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.146416

We previously reported heightened expression of the human endogenous retroviral protein HERV-K deoxyuridine triphosphate nucleotidohydrolase (dUTPase) in circulating monocytes and pulmonary arterial (PA) adventitial macrophages of patients with PA hypertension (PAH). Furthermore, recombinant HERV-K dUTPase increased IL-6 in PA endothelial cells (PAECs) and caused pulmonary hypertension in rats. Here we show that monocytes overexpressing HERV-K dUTPase, as opposed to GFP, can release HERV-K dUTPase in extracellular vesicles (EVs) that cause pulmonary hypertension in mice in association with endothelial mesenchymal transition (EndMT) related to induction of SNAIL/SLUG and proinflammatory molecules IL-6 as well as VCAM1. In PAECs, HERV-K dUTPase requires TLR4-myeloid differentiation primary response-88 to increase IL-6 and SNAIL/SLUG, and HERV-K dUTPase interaction with melanoma cell adhesion molecule (MCAM) is necessary to upregulate VCAM1. TLR4 engagement induces p-p38 activation of NF-κB in addition to p-pSMAD3 required for SNAIL and pSTAT1 for IL-6. HERV-K dUTPase interaction with MCAM also induces p-p38 activation of NF-κB in addition to pERK1/2-activating transcription factor-2 (ATF2) to increase VCAM1. Thus in PAH, monocytes or macrophages can release HERV-K dUTPase in EVs, and HERV-K dUTPase can engage dual receptors and signaling pathways to subvert PAEC transcriptional machinery to induce EndMT and associated proinflammatory molecules.