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Induction of Maternal Immune Activation in Mice at Mid-gestation Stage with Viral Mimic PolyI:C
Published on: March 25, 2016
Virus Mimetic Poly (I:C)-Primed Airway Exosome-like Particles Enter Brain and Induce Inflammatory Cytokines and
Deimantė Kulakauskienė1,2, Deimantė Narauskaitė1, Dovydas Gečys1,3
1Institute of Pharmaceutical Technologies, Faculty of Pharmacy, Lithuanian University of Health Sciences, LT-50162 Kaunas, Lithuania.
Abstract:
Viral infections induce extracellular vesicles (EVs) containing viral material and inflammatory factors. Exosomes can easily cross the blood-brain barrier during respiratory tract infection and transmit the inflammatory signal to the brain; however, such a hypothesis has no experimental evidence. The study investigated whether exosome-like vesicles (ELVs) from virus mimetic poly (I:C)-primed airway cells enter the brain and interact with brain immune cells microglia. Airway cells were isolated from Wistar rats and BALB/c mice; microglial cell cultures-from Wistar rats. ELVs from poly (I:C)-stimulated airway cell culture medium were isolated by precipitation, visualised by transmission electron microscopy, and evaluated by nanoparticle analyser; exosomal markers CD81 and CD9 were determined by ELISA. For in vitro and in vivo tracking, particles were loaded with Alexa Fluor 555-labelled RNA. Intracellular reactive oxygen species (ROS) were evaluated by DCFDA fluorescence and mitochondrial superoxide-by MitoSOX. ELVs from poly (I:C)-primed airway cells entered the brain within an hour after intranasal introduction, were internalised by microglia and induced intracellular and intramitochondrial ROS production. There was no ROS increase in microglial cells was after treatment with ELVs from airway cells untreated with poly (I:C). In addition, poly (I:C)-primed airway cells induced inflammatory cytokine expression in the brain. The data indicate that ELVs secreted by virus-primed airway cells might enter the brain, cause the activation of microglial cells and neuroinflammation.
Insights
Extracellular vesicles (EVs) from virus-stimulated airway cells cross the blood-brain barrier, activating brain immune cells and causing neuroinflammation. This study provides evidence for EVs transmitting inflammatory signals to the brain during respiratory infections.
Area of Science:
- Neuroimmunology
- Cell Biology
- Respiratory Medicine
Background:
- Viral infections trigger release of extracellular vesicles (EVs) carrying inflammatory factors.
- Exosomes are hypothesized to cross the blood-brain barrier during respiratory infections, transmitting inflammatory signals to the brain.
- Experimental evidence for this exosome-mediated neuroinflammation pathway is lacking.
Purpose of the Study:
- To investigate if exosome-like vesicles (ELVs) from virus-mimetic poly (I:C)-primed airway cells can enter the brain.
- To determine if these ELVs interact with brain immune cells, specifically microglia.
- To assess the impact of ELVs on microglial activation and neuroinflammation.
Main Methods:
- Airway cells and microglia were isolated from Wistar rats and BALB/c mice.
- ELVs were isolated from poly (I:C)-stimulated airway cell culture medium.
- ELVs were characterized using transmission electron microscopy, nanoparticle analysis, and ELISA for exosomal markers (CD81, CD9).
- In vitro and in vivo tracking utilized Alexa Fluor 555-labeled RNA-loaded particles.
- Reactive oxygen species (ROS) production in microglia was measured using DCFDA fluorescence and MitoSOX.
Main Results:
- ELVs from poly (I:C)-primed airway cells successfully entered the brain within one hour of intranasal administration.
- These ELVs were internalized by microglia.
- Internalization of ELVs induced significant intracellular and intramitochondrial ROS production in microglia.
- No ROS increase was observed when microglia were treated with ELVs from untreated airway cells.
- Poly (I:C)-primed airway cells induced inflammatory cytokine expression in the brain.
Conclusions:
- ELVs secreted by virus-primed airway cells can penetrate the blood-brain barrier.
- These ELVs activate microglia, leading to increased ROS production.
- The findings suggest a novel mechanism for neuroinflammation transmission from the respiratory tract to the brain via extracellular vesicles.
