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Monocytes Release Endogenous Retroviral Protein in Exosomes Causing a Mesenchymal, Proinflammatory Endothelium and Pulmonary Hypertension

ABSTRACT: Human endogenous retroviral (HERV) proteins are induced by exogenous viruses or other factors that derepress HERV transcription and translation. Previously we showed that HERV-K envelope and deoxyuridine triphosphate nucleotidohydrolase (dUTPase) proteins are increased in monocytes and macrophages from patients with pulmonary arterial hypertension (PAH). Recombinant HERV-K dUTPase upregulates IL6 in pulmonary arterial endothelial cells (PAECs) and induces pulmonary hypertension in rats. However, it was not known how HERV-K dUTPase released from monocytes engages PAECs to upregulate IL6 or induces other PAH features of PAEC dysfunction. Here we report that HERV-K dUTPase recruits TLR4-myeloid differentiation primary response-88 to increase IL6 and SNAIL, the endothelial-mesenchymal transition (EndMT) transcription factor; HERV-K dUTPase interaction with melanoma cell adhesion molecule (MCAM) upregulates VCAM1. p38 and NF-kB are required to increase expression of all three genes, but in addition, pJNK-pSMAD3 is necessary for SNAIL upregulation, STAT1 for IL6, and pERK1/2-activating transcription factor-2 for VCAM1. Packaging of HERV-K dUTPase in monocyte-derived extracellular vesicles (EVs) induces SNAIL and subsequent EndMT in PAECs, IL6 and VCAM1. Mice infused with EVs from monocytes transfected with HERV-K dUTPase develop pulmonary hypertension. Thus, retroviral proteins delivered in EVs can overtake PAEC signaling and transcriptional machinery to induce dysfunction associated with PAH.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Dr. Marlene Rabinovitch

PROVIDER: MSV000086005 | MassIVE | Mon Aug 24 10:40:00 BST 2020

REPOSITORIES: MassIVE

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Project description:Despite recent improvements in management of idiopathic pulmonary arterial hypertension, mortality remains high. Understanding the alterations in the transcriptome–phenotype of the key lung cells involved could provide insight into the drivers of pathogenesis. In this study, we examined differential gene expression of cell types implicated in idiopathic pulmonary arterial hypertension from lung explants of patients with idiopathic pulmonary arterial hypertension compared to control lungs. After tissue digestion, we analyzed all cells from three idiopathic pulmonary arterial hypertension and six control lungs using droplet-based single cell RNA-sequencing. After dimensional reduction by t-stochastic neighbor embedding, we compared the transcriptomes of endothelial cells, pericyte/smooth muscle cells, fibroblasts, and macrophage clusters, examining differential gene expression and pathways implicated by analysis of Gene Ontology Enrichment. We found that endothelial cells and pericyte/smooth muscle cells had the most differentially expressed gene profile compared to other cell types. Top differentially upregulated genes in endothelial cells included novel genes: ROBO4, APCDD1, NDST1, MMRN2, NOTCH4, and DOCK6, as well as previously reported genes: ENG, ORAI2, TFDP1, KDR, AMOTL2, PDGFB, FGFR1, EDN1, and NOTCH1. Several transcription factors were also found to be upregulated in idiopathic pulmonary arterial hypertension endothelial cells including SOX18, STRA13, LYL1, and ELK, which have known roles in regulating endothelial cell phenotype. In particular, SOX18 was implicated through bioinformatics analyses in regulating the idiopathic pulmonary arterial hypertension endothelial cell transcriptome. Furthermore, idiopathic pulmonary arterial hypertension endothelial cells upregulated expression of FAM60A and HDAC7, potentially affecting epigenetic changes in idiopathic pulmonary arterial hypertension endothelial cells. Pericyte/smooth muscle cells expressed genes implicated in regulation of cellular apoptosis and extracellular matrix organization, and several ligands for genes showing increased expression in endothelial cells. In conclusion, our study represents the first detailed look at the transcriptomic landscape across idiopathic pulmonary arterial hypertension lung cells and provides robust insight into alterations that occur in vivo in idiopathic pulmonary arterial hypertension lungs.

Project description:Rationale: Schistosomiasis is one of the most common causes of pulmonary arterial hypertension worldwide, but the pathogenic mechanism by which the host inflammatory response contributes to vascular remodeling is unknown. We sought to identify signaling pathways that play protective or pathogenic roles in experimental Schistosoma-induced pulmonary vascular disease by whole-lung transcriptome analysis. Methods: Wildtype mice were experimentally exposed to S. mansoni ova by intraperitoneal sensitization followed by tail vein augmentation, and the phenotype assessed by right ventricular catheterization and tissue histology, RNA and protein analysis. Whole-lung transcriptome analysis by microarray and RNA sequencing was performed, the latter analyzed using 2 bioinformatic methods. Functional testing of the candidate IL-6 pathway was determined using IL6-knockout mice and the STAT3 inhibitor STI-201. Results: Wild-type mice exposed to S. mansoni had increased right ventricular systolic pressure and thickness of the pulmonary vascular media. Whole lung transcriptome analysis identified the IL6-STAT3-NFATc2 pathway as being upregulated, which was confirmed by PCR and immunostaining of lung tissue from S. mansoni-exposed mice and patients who died of the disease. Mice lacking IL6 or treated with STI-201 developed pulmonary hypertension associated with significant intima remodeling after exposure to S. mansoni. Conclusions: Whole lung transcriptome analysis identified upregulation of the IL6-STAT3-NFATc2 pathway, and IL6 signaling was found to be protective against Schistosoma-induced intimal remodeling. Affy Mouse ST1.0 chip used. Data published in: Protective Role of IL6 in Vascular Remodeling in Schistosoma-Pulmonary Hypertension. Graham BB, Chabon J, Kumar R, Kolosionek E, Gebreab L, Debella E, Edwards M, Diener K, Shade T, Bifeng G, Bandeira A, Butrous G, Jones K, Geraci M, Tuder RM. Am J Respir Cell Mol Biol. 2013 Jul 1. [Epub ahead of print] PMID: 23815102

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Monocytes Release Endogenous Retroviral Protein in Exosomes Causing a Mesenchymal, Proinflammatory Endothelium and Pulmonary Hypertension

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