Endogenous Retroviral Elements Generate Pathologic Neutrophils in Pulmonary Arterial Hypertension

Taylor, Shalina; Isobe, Satoshi; Cao, Aiqin; Contrepois, Kévin; Benayoun, Bérénice A.; Jiang, Lihua; Wang, Lingli; Melemenidis, Stavros; Özen, Mehmet Özgün; Otsuki, Shoichiro; Shinohara, Tsutomu; Sweatt, Andrew J.; Kaplan, Jordan; Moonen, Jan-Renier; Marciano, David P.; Gu, Mingxia; Miyagawa, Kazuya; Hayes, Brandon; Sierra, Raymond G.; Kupitz, Christopher; Rosario, Patricia A. del; Hsi, Andrew; Thompson, A. A. Roger; Ariza, Maria E.; Demirci, Utkan; Zamanian, Roham T.; Haddad, François; Nicolls, Mark R.; Snyder, M; Rabinovitch, Marlene

doi:10.1164/rccm.202102-0446oc

Cited by 16 publications

(13 citation statements)

References 62 publications

(88 reference statements)

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“…Elevated circulating levels of neutrophils have been reported in PAH compared to control patients (9,27,40). Neutrophils may cause PAH through different mechanisms, namely by releasing neutrophil elastase (27) and myeloperoxidase, a catalyst for reactive oxygen species (ROS) formation (41). Our functional studies indicate that neutrophil-derived EVs, that are enriched in elastase (27) promote SMC proliferation, consistent with a mechanism previously demonstrated on elastase release of growth factors (23).…”

Section: Discussionmentioning

confidence: 99%

“…Their extramural localization correlated with SMC mass, likewise, increased in HPAH. Elevated circulating levels of neutrophils have been reported in PAH compared to control patients (9,27,40). Neutrophils may cause PAH through different mechanisms, namely by releasing neutrophil elastase (27) and myeloperoxidase, a catalyst for reactive oxygen species (ROS) formation (41).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to their pro-proliferative impact on PASMC, mo-DC also influence EC gene expression, by downregulating crucial EC markers involved in barrier function, such as PECAM and CDH5 (40). These alterations may affect the trans-endothelial migration of inflammatory cells in PAH (41), contributing to chronic inflammation maintenance.…”

Section: Discussionmentioning

confidence: 99%

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Single-Cell Imaging Maps Inflammatory Cell Subsets to Pulmonary Arterial Hypertension Vasculopathy

Ferrian

McCaffrey

Saito

et al. 2022

Preprint

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Experimental and clinical observations are advancing immunotherapies to clinical trial in pulmonary arterial hypertension (PAH). However, comprehensive mapping of the immune landscape in and around pulmonary arteries (PAs) in lung tissue is necessary to predict how immune cells might induce pulmonary vascular pathology. While more severe vascular pathology is reported in BMPR2 mutant patients classified as hereditary (H)PAH, the relationship to specific immune cell subsets has not been established. Emerging high throughput approaches such as multiplexed ion beam imaging by time-of-flight (MIBI-TOF) that labels antibodies with mass elements enables the study of multiple cells and states of activation in the same tissue section. Methods: We applied MIBI-TOF to compare PAs and surrounding tissue from unused donor lungs with PAH lungs that were diagnosed as idiopathic (IPAH) or HPAH. Measurements: We measured the number and proximity of immune cells to vascular lesions and to each other. Immune cell subsets that tracked with vascular pathology were interrogated ex vivo for stimulation of pulmonary arterial smooth muscle cell (PASMC) proliferation. Results: Extensive immune infiltration in I/HPAH was observed with intramural infiltration linked to PA occlusive changes. The presence of CD11c+DCs expressing SAMHD1, TIM-3 and IDO-1 within immune enriched microenvironments and neutrophils were associated with greater immune activation in HPAH. CD11c-DC3s (mo-DC-like cells) were linked to iNOS+ endothelial cells and proliferating SMCs. Co-culture studies reinforced a causal relationship between neutrophil extracellular vesicles and mo-DCs in mediating PASMC proliferation. Conclusions: These findings merit consideration in predicting and assessing the efficacy of immunotherapies for PAH.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Single-Cell Imaging Maps Inflammatory Cell Subsets to Pulmonary Arterial Hypertension Vasculopathy

Ferrian

McCaffrey

Saito

et al. 2022

Preprint

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“…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 ]. Increased production and release of elastase, neutrophil extracellular traps, and vinculin-mediated increased adhesion in PAH are attributed to an increased in HERV-K dUTPase [ 141 ]. Another example of pro-inflammatory potential of HERV-K dUTPase is psoriasis, where HERV-K dUTPase proteins induce the activation of NF-κB through TLR2 to trigger the secretion of TH1 and TH17 cytokines involved in the formation of psoriatic plaques, supporting HERV-K dUTPase as a potential contributor to psoriasis pathophysiology [ 142 ].…”

Section: Transcriptional Dysregulation Of Ervs In Human Diseasesmentioning

confidence: 99%

Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases

Zhang

Pan

Cong

et al. 2022

IJMS

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Endogenous retroviruses (ERVs), deriving from exogenous retroviral infections of germ line cells occurred millions of years ago, represent ~8% of human genome. Most ERVs are highly inactivated because of the accumulation of mutations, insertions, deletions, and/or truncations. However, it is becoming increasingly apparent that ERVs influence host biology through genetic and epigenetic mechanisms under particular physiological and pathological conditions, which provide both beneficial and deleterious effects for the host. For instance, certain ERVs expression is essential for human embryonic development. Whereas abnormal activation of ERVs was found to be involved in numbers of human diseases, such as cancer and neurodegenerative diseases. Therefore, understanding the mechanisms of regulation of ERVs would provide insights into the role of ERVs in health and diseases. Here, we provide an overview of mechanisms of transcriptional regulation of ERVs and their dysregulation in human diseases.

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“…9 Moreover, neutrophils isolated from circulating blood of patients with PAH have functional alterations, in that their transmigration is reduced while adhesion to pulmonary artery endothelial cells is increased. 10 Neutrophils isolated from patients with PAH have a capacity to release neutrophil elastase, and elevated elastase is associated with greater disease severity and increased mortality risk, possibly by dysregulating the BMPR2 (bone morphogenetic protein receptor 2) signaling pathway. 5,[11][12][13] Accordingly, the endogenous elastase inhibitor elafin has become a target-specific biomarker in clinical trials.…”

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confidence: 99%

Single-Cell Transcriptome Analysis of Peripheral Neutrophils From Patients With Idiopathic Pulmonary Arterial Hypertension

Wang

Zhang²,

Zhang

et al. 2023

Hypertension

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BACKGROUND: Idiopathic pulmonary hypertension (IPAH) is a rare and devastating disease often accompanied by persistent inflammation and immune responses. We aim to provide a reference atlas of neutrophils to facilitate a better understanding of cellular phenotypes and discovery of candidate genes. METHODS: Peripheral neutrophils from naive patients with IPAH and matched controls were profiled. Whole-exon sequencing was performed to exclude known genetic mutations before establishing single-cell RNA sequencing. Marker genes were validated by flow cytometry and histology in a separate validation cohort. RESULTS: Seurat clustering analysis revealed that the landscape of neutrophils encompassed 5 clusters, including 1 progenitor, 1 transition, and 3 functional clusters. The intercorrelated genes in patients with IPAH were mainly enriched in antigen processing presentation and natural killer cell mediated cytotoxicity. We identified and validated differentially upregulated genes, including matrix metallopeptidase 9 ( MMP9 ), ISG15 ubiquitin-like modifier ( ISG15 ), and C-X-C motif ligand 8 ( CXCL8 ). The positive proportions and fluorescence quantification of these genes were significantly increased in CD16 + neutrophils in patients with IPAH. The higher proportion of positive MMP9 (matrix metallopeptidase 9) neutrophils increased mortality risk after adjustment for age and sex. Patients with higher proportions of positive MMP9 neutrophils had worse survival, while the fraction of ISG15- or C-X-C motif chemokine ligand 8-positive expression neutrophils failed to predict outcome. CONCLUSIONS: Our study yields a comprehensive dataset of the landscape of neutrophils in patients with IPAH. The predictive values of a neutrophil cluster characterized by higher MMP9 expression indicate a functional role for neutrophil-specific matrix metalloproteinases in the pathogenesis of pulmonary arterial hypertension.

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Endogenous Retroviral Elements Generate Pathologic Neutrophils in Pulmonary Arterial Hypertension

Abstract: ST and MR conceptualized the project. ST performed experiments, analyzed data, edited the figures, and wrote the manuscript. SI performed experiments and analyzed AJRCCM Articles in Press.

Cited by 16 publications

References 62 publications

Single-Cell Imaging Maps Inflammatory Cell Subsets to Pulmonary Arterial Hypertension Vasculopathy

Single-Cell Imaging Maps Inflammatory Cell Subsets to Pulmonary Arterial Hypertension Vasculopathy

Transcriptional Regulation of Endogenous Retroviruses and Their Misregulation in Human Diseases

Single-Cell Transcriptome Analysis of Peripheral Neutrophils From Patients With Idiopathic Pulmonary Arterial Hypertension

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