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

Abstract

Previously we reported heightened expression of human endogenous retroviral protein HERV-K deoxyuridine triphosphate nucleotidohydrolase (dUTPase) in circulating monocytes and pulmonary arterial (PA) adventitial macrophages of PA hypertension (PAH) patients. Furthermore, recombinant HERV-K dUTPase increased IL6 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 IL6 as well as VCAM1. In PAECs, HERV-K dUTPase requires TLR4myeloid differentiation primary response (MYD)-88 to increase IL6 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 pJNK-pSMAD3 required for SNAIL, and pSTAT1 for IL6. HERV-K dUTPase interaction with MCAM also induces p-p38 activation of NF-κB in addition to pERK1/2-activating transcription factor (ATF)-2 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 pro-inflammatory molecules.

Endogenous Retroviral Elements Generate Pathologic Neutrophils in Pulmonary Arterial Hypertension

“…HERV-K dUTPase did not induce an elevation in PKR or RIG-1 mRNA or in NE protein (Figure E5C and E5D in the Online Data Supplement). The dose of dUTPase chosen was based upon previous studies by our group showing the impact of dUTPase on cytokine release (37) and EndMT (38). We then determined whether the increase in vinculin could explain the increase in adhesion and the reduction in migration.…”

Transcription factors in the pathogenesis of pulmonary arterial hypertension—Current knowledge and therapeutic potential

“…In advanced PAH, NF-κB is active in PAEC, PASMC and perivascular macrophages and lymphocytes of large and small pre-capillary vessels and is correlated with expression of pro-inflammatory cytokines (131). In PAEC, NF-κB contributes to leucocyte adhesion and inflammation facilitating EndMT (132). In contrast, genetic and pharmacological inhibition of NF-κB reversed and prevented experimental PAH in rodent models, respectively (133,134).…”

“…This results in a proliferative, hypermigratory phenotype (138). Also Otsuki et al showed, that PAECs stimulated with human endogenous retrovirus K (HERV-K) dUTPase have a TLR4-STAT1-dependent inflammatory response (132).…”

Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases

“…HERV deoxyuridine triphosphate nucleotidohydrolase (dUTPase) can trigger innate and adaptive immune responses [ 139 ]. In pulmonary arterial hypertension (PAH), the HERV-K dUTPase activates B cells, elevates cytokines in monocytes and pulmonary arterial endothelial cells, and increases pulmonary artery vulnerability to apoptosis, contributing to sustained inflammation and immune dysregulation [ 140 ].…”