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Cited by 412Extracellular vesicles in diseaseNeuroinflammation and Neurodegeneration MechanismsBarrier Structure and Function Studies

Extracellular Vesicle-Mediated Transfer of Genetic Information between the Hematopoietic System and the Brain in Response to Inflammation

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Ridder, Kirsten, Keller, Sascha, Dams, Maria, Rupp, Anne-Kathleen, Schlaudraff, Jessica, Del Turco, Domenico, Starmann, Julia, Macas, Jadranka +10 more·2014·PLoS Biology
DOI 10.1371/journal.pbio.1001874PMC PMC4043485
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Abstract

Mechanisms behind how the immune system signals to the brain in response to systemic inflammation are not fully understood. Transgenic mice expressing Cre recombinase specifically in the hematopoietic lineage in a Cre reporter background display recombination and marker gene expression in Purkinje neurons. Here we show that reportergene expression in neurons is caused by intercellular transfer of functional Cre recombinase messenger RNA from immune cells into neurons in the absence of cell fusion. In vitro purified secreted extracellular vesicles (EVs) from blood cells contain Cre mRNA, which induces recombination in neurons when injected into the brain. Although Cre-mediated recombination events in the brain occur very rarely in healthy animals, their number increases considerably in different injury models, particularly under inflammatory conditions, and extend beyond Purkinje neurons to other neuronal populations in cortex, hippocampus, and substantia nigra. Recombined Purkinje neurons differ in their miRNA profile from their nonrecombined counterparts, indicating physiological significance. These observations reveal the existence of a previously unrecognized mechanism to communicate RNA-based signals between the hematopoietic system and various organs, including the brain, in response to inflammation.

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Crossref · 10.1371/journal.pbio.1001874

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  • Recent findings of a long-range crosstalk between periphery and CNS via miRNA-containing exosomes position the BBB in the center of this communication under physiological and pathophysiological conditions.

    “Recent findings of a long-range crosstalk between periphery and CNS via miRNA-containing exosomes position the BBB in the center of this communication (685) under physiological (635, 660) and pathophysiological (378, 493, 498, 587) conditions.”

    From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [498]

    The Results section, “EVs Targeting Neurons May Enter the Brain Via the Circulation” (page unavailable), reports that bone-marrow EVs increased permeability in an in-vitro BBB model. The Discussion describes crossing the BBB as a key question in blood-to-brain EV transfer, supporting the BBB’s relevance to the proposed communication. But it explicitly says the findings are not formal proof of direct miRNA transfer via EVs, so the claim’s assertion of crosstalk *via miRNA-containing exosomes* is stronger than the evidence. The physiological and pathophysiological conditions are attached to other citations in the citing sentence. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The blood-brain barrier is highly vulnerable to penetration by exosomes.

    “It is worth noting that the blood–brain barrier (BBB) is highly vulnerable to penetration by EXO [18].”

    From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [18]

    In Results (‘EVs Targeting Neurons May Enter the Brain Via the Circulation’; page not provided), bone-marrow extracellular vesicles transiently increased the permeability of an in vitro BBB model. The Discussion describes entry from the circulation as a likely route, not an established general vulnerability of the BBB to exosome penetration. ‘Highly vulnerable’ overstates these qualified findings. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Exosomes can cross the blood-brain barrier and have a role in transfer of genetic information from peripheral hematopoietic cells and in inducing neuroinflammation in the brain.

    “EXO can cross the BBB and have been shown to have a role in the transfer of genetic information from peripheral hematopoietic cells and to induce neuroinflammation in the brain [18].”

    From Oral Microbially-Induced Small Extracellular Vesicles Cross the Blood–Brain Barrier (2024) · cites this paper as [18]

    The Discussion reports that hematopoietic-cell EVs, including exosomes, transfer functional RNA to brain neurons. Its Figure 8 presents crossing the blood–brain barrier as a possible route, not an established one. The Results report that inflammation increases neuronal transfer; they do not show that exosomes induce neuroinflammation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cited by

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Authors
Ridder, K., Keller, S., Dams, M., Rupp, A.-K., Schlaudraff, J., Del Turco, D., Starmann, J., Macas, J., Karpova, D., Devraj, K., Depboylu, C., Landfried, B., Arnold, B., Plate, K. H., Höglinger, G., Sültmann, H., Altevogt, P., & Momma, S.
Affiliations
  • Goethe University Frankfurt (DE)
  • German Cancer Research Center (DE)
  • Philipps University of Marburg (DE)
Corresponding author
Momma, Stefan
ORCID
Venue
PLoS Biology
Publisher
Public Library of Science (PLoS)
Published
2014-06-03
Volume
12
Issue
6
Pages
e1001874
ISSN
  • 1544-9173 (ISSN-L)
  • 1545-7885
DOI
10.1371/journal.pbio.1001874
PMC
PMC4043485
OpenAlex
W2166370479
Cited by
412
References
9
Citations by year
2026: 18 · 2025: 29 · 2024: 50 · 2023: 24 · 2022: 39 · 2021: 59 · 2020: 41 · 2019: 36 · 2018: 31 · 2017: 28 · 2016: 33 · 2015: 18 · 2014: 6
FWCI
11.62
Type
journal article
Language
en
Update notices
correction (2018-03-12)
Open access
Licence
Locations
  • PLoS Biology (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Publication Server of Goethe University Frankfurt am Main (Goethe University Frankfurt) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • mediaTUM (Technical University of Munich) (submittedVersion)
  • DZNE Pub (submittedVersion, other-oa)
  • DZNE Pub (submittedVersion)
Funders
Deutsche Forschungsgemeinschaft
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
Keywords
extracellular vesicles, Cre recombinase, hematopoietic system, brain, systemic inflammation, intercellular RNA transfer, Purkinje cells, neuroimmune interactions, microRNA, Cre reporter mice, injury models, substantia nigra, hippocampus, cortex
MeSH terms
Animals, Hematopoietic System, Inflammation, Mice, Transgenic, Purkinje Cells, Recombination, Genetic, RNA, Messenger, Integrases, Exosomes

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