Evidence map›Paper›PMID 39375720›Full record

ArticleJournal of neuroinflammation2024

Extracellular vesicles in sepsis plasma mediate neuronal inflammation in the brain through miRNAs and innate immune signaling.

Chanhee Park, Zhuofan Lei, Yun Li, Boyang Ren, Junyun He, Huang Huang, Fengqian Chen, Hui Li, Kavitha Brunner, Jing Zhu and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of neuroinflammation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
20citing papers in PubMed, 1 pooled it
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

20 citing papers in PubMed, 1 synthesis or guideline pooled it.

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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors.

Chanhee ParkCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Zhuofan LeiCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Yun LiCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Boyang RenCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Junyun HeCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Huang HuangCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Fengqian ChenCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Hui LiCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Kavitha BrunnerCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Jing ZhuCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Steven M JayFischell Department of Bioengineering, University of Maryland, College Park, MD, 20740, USA.
Brittney WilliamsCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Wei ChaoCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA.
Junfang WuCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. junfang.wu@som.umaryland.edu.
Lin ZouCenter for Shock, Trauma and Anesthesiology Research, University of Maryland School of Medicine, Baltimore, MD, 21201, USA. lzou@som.umaryland.edu.

Funding

Dementia Following Spinal Cord Injury: Mechanism and Therapeutic TargetingRF1NS110637 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI JAY, STEVEN MICHAEL, WU, JUNFANG · 2019 to 2019
$2.8M
Targeting brain inflammation and neurocognitive dysfunction in sepsisR01NS110567 · NINDS · UNIVERSITY OF MARYLAND BALTIMORE · PI CHAO, WEI, WU, JUNFANG · 2019 to 2024
$2.5M
NIA NIH HHS RF1NS110637NINDS NIH HHS R01 NS110567NINDS NIH HHS R01NS110567NINDS NIH HHS RF1 NS110637
6 · The paper itself

Abstract

backgroundNeuroinflammation 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.

methodsTo 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.

resultsWe 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.

conclusionsCirculating 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.

Indexed as

BrainExtracellular VesiclesImmunity, InnateMice, Inbred C57BLMice, KnockoutMicroRNAsNeuronsSepsisSignal TransductionAnimalsHEK293 CellsHumansInflammationMaleMembrane GlycoproteinsMiceMembrane GlycoproteinsMicroRNAsMyeloid Differentiation Factor 88Tlr7 protein, mouseToll-Like Receptor 7Extracellular miRNAExtracellular vesicles (EVs)MicrogliaMyeloid differentiation primary response 88 (MyD88)NeuroinflammationNeuronal apoptosisSepsisSepsis-associated encephalopathy (SAE)Toll-like receptor 7 (TLR7)

Identifiers

PMID39375720
PMCPMC11460013

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.