4.6 Article

Platelet Microparticles Enriched in miR-223 Reduce ICAM-1-Dependent Vascular Inflammation in Septic Conditions

Journal

FRONTIERS IN PHYSIOLOGY
Volume 12, Issue -, Pages -

Publisher

FRONTIERS MEDIA SA
DOI: 10.3389/fphys.2021.658524

Keywords

platelet; endothelial cell; microRNA; miR-223; sepsis; microparticle; ICAM-1

Categories

Funding

  1. European Union
  2. European Reginal Development Fund
  3. Lajos Szodoray Grant
  4. OTKA Bridging Fund (General Medicine Faculty of University of Debrecen)
  5. Debrecen Venture Catapult program [EFOP-3.6.1-16-2016-00022]
  6. New National Excellence Program of the Ministry for Innovation and Technology [UNKP-20-4-II-DE-197]
  7. [GINOP-2.3.2-15-2016-00043]

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The study revealed that activated platelets transfer miR-223 to endothelial cells via microparticles during sepsis, leading to a decrease in ICAM-1 expression. This protective mechanism may help regulate excessive sepsis-induced vascular inflammation.
In the process of sepsis, activated platelets shed microvesicles containing microRNAs (miRNAs), which can be internalized by distinct recipient cells in circulation, consequently eliciting a potent capability to regulate their cellular functions in different diseases. In the present study, activated human platelets transferring miR-223 into endothelial cells via platelet-derived microparticles (PMPs) was investigated in vitro during septic conditions with a proposed mechanism involving in downregulation of the enhanced expression of intercellular adhesion molecule-1 (ICAM-1). The uptake of PMPs encasing miR-223 and the adhesion of peripheral blood mononuclear cells (PBMCs) on human coronary artery endothelial cells (HCAECs) were observed by immunofluorescence microscopy upon co-culture with PMPs isolated from sepsis or control plasma. The expression of miR-223-3p and its gene target ICAM1 in HCAECs were quantified by RT-qPCR and ELISA after the cells were incubated with septic or control PMPs, whose levels were induced with thrombin-receptor activating peptide (TRAP). Leukocyte-depleted platelets (LDPs) from septic patients showed a decreased miR-223 level, while septic plasma and PMPs revealed an elevated miRNA level compared to control samples. Similarly, TRAP-activated LDPs demonstrated a reduced intracellular miR-223 expression, while increased levels in the supernatant and PMP isolates were observed vs. untreated samples. Furthermore, TNF-alpha alone resulted in decreased miR-223 and elevated ICAM1 levels in HCAECs, while PMPs raised the miRNA level that was associated with downregulated ICAM1 expression at both mRNA and protein levels under TNF-alpha treatment. Importantly, miR-223 was turned out not to be newly synthesized as shown in unchanged pre-miR-223 level, and mature miR-223 expression was also elevated in the presence of PMPs in HCAECs after transfection with Dicer1 siRNA. In addition, septic PMPs containing miR-223 decreased ICAM1 with a reduction of PBMC binding to HCAECs. In conclusion, septic platelets released PMPs carrying functional miR-223 lower ICAM1 expression in endothelial cells, which may be a protective role against excessive sepsis-induced vascular inflammation.

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