3 years ago

Interferon regulatory factor 1-Rab27a regulated extracellular vesicles promote liver ischemia/reperfusion injury.

Timothy R Billiar, Donna B Stolz, Qiang Du, Rong-Hua Wang, Adrian E Morelli, Bin Chen, Mu-Qing Yang, Patrick R Varley, Julie Goswami, David A Geller, Jiyu Li
The role and regulators of extracellular vesicles (EV) secretion in hepatic ischemia/reperfusion (IR) injury have not been defined. Rab27a is a GTPase known to control EVs release. Interferon regulatory factor 1 (IRF-1) is a transcription factor that plays an important role in liver IR and regulates certain GTPases. However, the relationships among IRF-1, Rab27a, and EVs secretion are largely unknown. Here, we show induction of IRF-1 and Rab27a both in vitro in hypoxic hepatocytes and in vivo in warm IR and orthotopic liver transplantation livers. Interferon γ stimulation, IRF-1 transduction, or IR promoted Rab27a expression and EVs secretion. Meanwhile, silencing of IRF-1 decreased Rab27a expression and EVs secretion. Rab27a silencing decreased EVs secretion and liver IR injury. Ten putative IRF-1 binding motifs in the 1,692 base pairs Rab27a promoter region were identified. Chromatin immunoprecipitation and electrophoretic mobility shift assay verified five functional IRF-1 binding motifs, which were confirmed by Rab27a promoter luciferase assay. IR-induced EVs contained higher oxidized phospholipids (OxPL). OxPLs on EVs surface activated neutrophil through toll like receptor 4 (TLR-4) pathway. OxPL-neutralizing E06 antibody blocked the effect of EVs and decreased liver IR injury. These findings provide a novel mechanism by which IRF-1 regulates Rab27a transcription and EVs secretion, leading to OxPL activation of neutrophils and subsequent hepatic IR injury. This article is protected by copyright. All rights reserved.

Publisher URL: http://doi.org/10.1002/hep.29605

DOI: 10.1002/hep.29605

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