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Extracellular vesicles in sepsis plasma mediate neuronal inflammation in the brain through miRNAs and innate immune signaling
Author
Park, ChanheeLei, Zhoufan
Li, Yun
Ren, Boyang
He, Junyun
Huang, Huang
Chen, Fengqian
Li, Hui
Brunner, Kavitha
Zhu, Jing
Jay, Steven M.
Williams, Brittney
Chao, Wei
Wu, Junfang
Zou, Lin
Date
2024-10-07Journal
Journal of NeuroinflammationPublisher
Springer NatureType
Article
Metadata
Show full item recordAbstract
Background Neuroinflammation reportedly plays a critical role in the pathogenesis of sepsis-associated encephalopathy (SAE). We previously reported that circulating plasma extracellular vesicles (EVs) from septic mice are proinflammatory. In the current study, we tested the role of sepsis plasma EVs in neuroinflammation. Methods To track EVs in cells and tissues, HEK293T cell-derived EVs were labeled with the fluorescent dye PKH26. Cecal ligation and puncture (CLP) was conducted to model polymicrobial sepsis in mice. Plasma EVs were isolated by ultracentrifugation and their role in promoting neuronal inflammation was tested following intracerebroventricular (ICV) injection. miRNA inhibitors (anti-miR-146a, -122, -34a, and -145a) were applied to determine the effects of EV cargo miRNAs in the brain. A cytokine array was performed to profile microglia-released protein mediators. TLR7- or MyD88-knockout (KO) mice were utilized to determine the underlying mechanism of EVs-mediated neuroinflammation. Results We observed the uptake of fluorescent PKH26-EVs inside the cell bodies of both microglia and neurons. Sepsis plasma EVs led to a dose-dependent cytokine release in cultured microglia, which was partially attenuated by miRNA inhibitors against the target miRNAs and in TLR7-KO cells. When administered via the ICV, sepsis plasma EVs resulted in a marked increase in the accumulation of innate immune cells, including monocyte and neutrophil and cytokine gene expression, in the brain. Although sepsis plasma EVs had no direct effect on cytokine production or neuronal injury in vitro, the conditioned media (CM) of microglia treated with sepsis plasma EVs induced neuronal cell death as evidenced by increased caspase-3 cleavage and Annexin-V staining. Cytokine arrays and bioinformatics analysis of the microglial CM revealed multiple cytokines/chemokines and other factors functionally linked to leukocyte chemotaxis and migration, TLR signaling, and neuronal death. Moreover, sepsis plasma EV-induced brain inflammation in vivo was significantly dependent on MyD88. Conclusions Circulating plasma EVs in septic mice cause a microglial proinflammatory response in vitro and a brain innate immune response in vivo, some of which are in part mediated by TLR7 in vitro and MyD88 signaling in vivo. These findings highlight the importance of circulating EVs in brain inflammation during sepsis.Data Availibility
No datasets were generated or analysed during the current study.Description
The article processing charges (APC) for this open access article were partially funded by the Health Sciences and Human Services Library's Open Access Publishing Fund for Early-Career Researchers.Citation
Park, C., Lei, Z., Li, Y., Ren, B., He, J., Huang, H., Chen, F., Li, H., Brunner, K., Zhu, J., Jay, S. M., Williams, B., Chao, W., Wu, J., & Zou, L. (2024). Extracellular vesicles in sepsis plasma mediate neuronal inflammation in the brain through mirnas and innate immune signaling. Journal of Neuroinflammation, 21(1). https://doi.org/10.1186/s12974-024-03250-0Rights/Terms
Attribution-NonCommercial-NoDerivatives 4.0 InternationalKeyword
Neuroinflammatory DiseasesSepsis-Associated Encephalopathy
Sepsis
Extracellular Vesicles
Microglia
Identifier to cite or link to this item
http://hdl.handle.net/10713/22885ae974a485f413a2113503eed53cd6c53
10.1186/s12974-024-03250-0
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- Creative Commons
Except where otherwise noted, this item's license is described as Attribution-NonCommercial-NoDerivatives 4.0 International