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Exosomally Targeting microRNA23a Ameliorates Microvascular Endothelial Barrier Dysfunction Following Rickettsial
Changcheng Zhou1, Jiani Bei1, Yuan Qiu1
1Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States.
Abstract:
Spotted fever group rickettsioses caused by Rickettsia (R) are devastating human infections, which mainly target microvascular endothelial cells (ECs) and can induce lethal EC barrier dysfunction in the brain and lungs. Our previous evidence reveals that exosomes (Exos) derived from rickettsial-infected ECs, namely R-ECExos, can induce disruption of the tight junctional (TJ) protein ZO-1 and barrier dysfunction of human normal recipient brain microvascular endothelial cells (BMECs). However, the underlying mechanism remains elusive. Given that we have observed that microRNA23a (miR23a), a negative regulator of endothelial ZO-1 mRNA, is selectively sorted into R-ECExos, the aim of the present study was to characterize the potential functional role of exosomal miR23a delivered by R-ECExos in normal recipient BMECs. We demonstrated that EC-derived Exos (ECExos) have the capacity to deliver oligonucleotide RNAs to normal recipient BMECs in an RNase-abundant environment. miR23a in ECExos impairs normal recipient BMEC barrier function, directly targeting TJ protein ZO-1 mRNAs. In separate studies using a traditional in vitro model and a novel single living-cell biomechanical assay, our group demonstrated that miR23a anti-sense oligonucleotide-enriched ECExos ameliorate R-ECExo-provoked recipient BMEC dysfunction in association with stabilization of ZO-1 in a dose-dependent manner. These results suggest that Exo-based therapy could potentially prove to be a promising strategy to improve vascular barrier function during bacterial infection and concomitant inflammation.
Insights
Exosomes from Rickettsia-infected cells deliver microRNA-23a, disrupting endothelial barrier function by targeting ZO-1. Exosome-based therapy shows promise for treating bacterial infections and inflammation.
Area of Science:
- Cell Biology
- Molecular Biology
- Infectious Diseases
Background:
- Spotted fever group rickettsioses severely impact human health, targeting microvascular endothelial cells and causing lethal barrier dysfunction.
- Rickettsia-infected cell-derived exosomes (R-ECExos) induce brain microvascular endothelial cell (BMEC) barrier dysfunction by disrupting tight junction protein ZO-1.
- The precise mechanism by which R-ECExos cause barrier dysfunction remains unclear.
Purpose of the Study:
- To investigate the functional role of exosomal microRNA-23a (miR23a) delivered by R-ECExos in normal recipient BMECs.
- To elucidate the mechanism of exosome-mediated endothelial barrier dysfunction.
Main Methods:
- Demonstrated the capacity of endothelial cell-derived exosomes (ECExos) to deliver oligonucleotide RNAs to recipient BMECs in an RNase-rich environment.
- Utilized in vitro models and a novel single living-cell biomechanical assay.
- Investigated the effect of miR23a and miR23a anti-sense oligonucleotides within exosomes on BMEC barrier function and ZO-1 expression.
Main Results:
- Exosomal miR23a delivered by R-ECExos impairs normal BMEC barrier function by directly targeting ZO-1 mRNA.
- miR23a in ECExos leads to decreased ZO-1 levels and compromised endothelial barrier integrity.
- Enriching ECExos with miR23a anti-sense oligonucleotides ameliorated R-ECExo-induced BMEC dysfunction and stabilized ZO-1 in a dose-dependent manner.
Conclusions:
- Exosomal miR23a plays a critical role in mediating Rickettsia-induced endothelial barrier dysfunction.
- Exosome-based therapeutic strategies hold potential for restoring vascular barrier function during bacterial infections and inflammation.
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