PMID- 36061862
OWN - NLM
STAT- MEDLINE
DCOM- 20220908
LR  - 20220920
IS  - 2235-2988 (Electronic)
IS  - 2235-2988 (Linking)
VI  - 12
DP  - 2022
TI  - Human endothelial cell-derived exosomal microRNA-99a/b drives a sustained 
      inflammatory response during sepsis by inhibiting mTOR expression.
PG  - 854126
LID - 10.3389/fcimb.2022.854126 [doi]
LID - 854126
AB  - The pathophysiology of sepsis and its accompanying hyper-inflammatory response 
      are key events that lead to multi-organ failure and death. A growing body of 
      literature now suggests that the vascular endothelium plays a critical role in 
      driving early events of sepsis progression. In this study, we demonstrate how 
      endothelial-derived exosomes contribute to a successive pro-inflammatory 
      phenotype of monocytes. Exosomes isolated from S. aureus infected endothelial 
      cells drive both CD11b and MHCII expression in monocytes and contribute 
      dysregulated cytokine production. Conversely, healthy endothelial exosomes had no 
      major effect. microRNA (miRNA) profiling of exosomes identified miR-99 
      upregulation which we hypothesised as driving this phenotypic change through 
      mechanistic target of rapamycin (mTOR). Knockdown of mTOR with miR-99a and 
      miR-99b mimetics in S. aureus infected monocytes increased IL-6 and decreased 
      IL-10 production. Interestingly, inhibition of miRNAs with antagomirs has the 
      opposing effect. Collectively, endothelial exosomes are driving a 
      pro-inflammatory phenotype in monocytes through dysregulated expression of 
      miR-99a and miR-99b.
CI  - Copyright (c) 2022 Fitzpatrick, Nader, Watkin, McCoy, Curley and Kerrigan.
FAU - Fitzpatrick, Glenn
AU  - Fitzpatrick G
AD  - Cardiovascular Infection Research Group, Dublin, Ireland.
AD  - School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and 
      Health Sciences, Dublin, Ireland.
FAU - Nader, Danielle
AU  - Nader D
AD  - Cardiovascular Infection Research Group, Dublin, Ireland.
AD  - School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and 
      Health Sciences, Dublin, Ireland.
FAU - Watkin, Rebecca
AU  - Watkin R
AD  - Cardiovascular Infection Research Group, Dublin, Ireland.
AD  - School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and 
      Health Sciences, Dublin, Ireland.
FAU - McCoy, Claire E
AU  - McCoy CE
AD  - School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and 
      Health Sciences, Dublin, Ireland.
FAU - Curley, Gerard F
AU  - Curley GF
AD  - Department of Anaesthesia and Critical Care Medicine, RCSI University of Medicine 
      and Health Sciences, Beaumont Hospital, Dublin, Ireland.
FAU - Kerrigan, Steven W
AU  - Kerrigan SW
AD  - Cardiovascular Infection Research Group, Dublin, Ireland.
AD  - School of Pharmacy and Biomolecular Sciences, RCSI University of Medicine and 
      Health Sciences, Dublin, Ireland.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220818
PL  - Switzerland
TA  - Front Cell Infect Microbiol
JT  - Frontiers in cellular and infection microbiology
JID - 101585359
RN  - 0 (MIRN99 microRNA, human)
RN  - 0 (MicroRNAs)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Endothelial Cells/metabolism
MH  - *Exosomes/metabolism
MH  - Humans
MH  - MicroRNAs/genetics/*metabolism
MH  - *Sepsis/genetics/metabolism/pathology
MH  - Staphylococcus aureus/genetics
MH  - TOR Serine-Threonine Kinases/*genetics
PMC - PMC9434345
OTO - NOTNLM
OT  - endothelial cell
OT  - exosomes
OT  - infection
OT  - inflammation
OT  - mTOR
OT  - microRNA
OT  - sepsis
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2022/09/06 06:00
MHDA- 2022/09/09 06:00
PMCR- 2022/01/01
CRDT- 2022/09/05 04:15
PHST- 2022/01/14 00:00 [received]
PHST- 2022/07/18 00:00 [accepted]
PHST- 2022/09/05 04:15 [entrez]
PHST- 2022/09/06 06:00 [pubmed]
PHST- 2022/09/09 06:00 [medline]
PHST- 2022/01/01 00:00 [pmc-release]
AID - 10.3389/fcimb.2022.854126 [doi]
PST - epublish
SO  - Front Cell Infect Microbiol. 2022 Aug 18;12:854126. doi: 
      10.3389/fcimb.2022.854126. eCollection 2022.