Dataset Information

Human Neutrophils in Pulmonary Arterial Hypertension by LC-MSMS

ABSTRACT: Neutrophil elastase (NE) is implicated in pulmonary arterial hypertension (PAH) but the role of neutrophils in the pathogenesis of PAH is unclear. Here we show that neutrophils from PAH vs. control subjects produce and release increased NE associated with enhanced extracellular trap formation. PAH neutrophils are highly adherent and show decreased migration consistent with increased vinculin, identified on proteomic analysis and previously linked to an antiviral response. This was substantiated by a transcriptomic interferon signature in PAH neutrophils and an increase in human endogenous retrovirus (HERV-K) envelope protein. NE and interferon genes are induced by HERV-K envelope and vinculin is increased by HERV-K dUTPase that is elevated in PAH plasma. Neutrophil exosomes from PAH plasma contain increased NE and HERV-K envelope and induce pulmonary hypertension in mice, that is mitigated by the NE inhibitor and antiviral agent, elafin. Thus elevated HERVs explain pathological neutrophils linked to PAH induction and progression.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neutrophil

DISEASE(S): Pulmonary Hypertension

SUBMITTER: Shalina Taylor

LAB HEAD: Lihua Jiang

PROVIDER: PXD023134 | Pride | 2023-03-11

REPOSITORIES: Pride

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Publications

Endogenous Retroviral Elements Generate Pathologic Neutrophils in Pulmonary Arterial Hypertension.

Taylor Shalina S Isobe Sarasa S Cao Aiqin A Contrepois Kévin K Benayoun Bérénice A BA Jiang Lihua L Wang Lingli L Melemenidis Stavros S Ozen Mehmet O MO Otsuki Shoichiro S Shinohara Tsutomu T Sweatt Andrew J AJ Kaplan Jordan J Moonen Jan-Renier JR Marciano David P DP Gu Mingxia M Miyagawa Kazuya K Hayes Brandon B Sierra Raymond G RG Kupitz Christopher J CJ Del Rosario Patricia A PA Hsi Andrew A Thompson A A Roger AAR Ariza Maria E ME Demirci Utkan U Zamanian Roham T RT Haddad Francois F Nicolls Mark R MR Snyder Michael P MP Rabinovitch Marlene M

American journal of respiratory and critical care medicine 20221001 8

Rationale: The role of neutrophils and their extracellular vesicles (EVs) in the pathogenesis of pulmonary arterial hypertension is unclear. Objectives: To relate functional abnormalities in pulmonary arterial hypertension neutrophils and their EVs to mechanisms uncovered by proteomic and transcriptomic profiling. Methods: Production of elastase, release of extracellular traps, adhesion, and migration were assessed in neutrophils from patients with pulmonary arterial hyperte ...[more]

PMID: 35696338

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