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Short report
Li-Na Wei
University of Minnesota Twin Cities Campus: University of Minnesota
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6376-8506
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Intercellular communications are important for maintaining normal physiological processes. An important intercellular communication is mediated by the exchange of membrane-enclosed extracellular vesicles. Among various vesicles, exosomes can be detected in a wide variety of biological systems, but the regulation and biological implication of exosome secretion/uptake remains largely unclear.
Methods: Cellular retinoic acid (RA) binding protein 1 (Crabp1) knockout (CKO) mice were used for in vivo studies. Extracellular exosomes were monitored in CKO mice and relevant cell cultures including embryonic stem cell (CJ7), macrophage (Raw 264.7) and hippocampal cell (HT22) using Western blot and flow cytometry. Receptor Interacting Protein 140 (RIP140) was depleted by Crispr/Cas9-mediated gene editing. Anti-inflammatory maker was analyzed using qRT-PCR. Clinical relevance was accessed by mining multiple clinical datasets.
Results: This study uncovers Crabp1 as a negative regulator of exosome secretion from neurons. Specifically, RIP140, a pro-inflammatory regulator, can be transferred from neurons, via Crabp1-regulated exosome secretion, into macrophages to promote their inflammatory polarization. Consistently, CKO mice, defected in the negative control of exosome secretion, have significantly elevated RIP140-containing exosomes in their blood and cerebrospinal fluid, and exhibit an increased vulnerability to systemic inflammation. Clinical relevance of this pathway is supported by patients’ data of multiple inflammatory diseases. Further, the action of Crabp1 in regulating exosome secretion involves its ligand and is mediated by its downstream target, the MAPK signaling pathway.
Conclusions: This study presents the first evidence for the regulation of exosome secretion, which mediates intercellular communication, by RA-Crabp1 signaling. This novel mechanism can contribute to the control of systemic inflammation by transferring an inflammatory regulator, RIP140, between cells. This represents a new mechanism of vitamin A action that can modulate the homeostasis of system-wide innate immunity without involving gene regulation.
Keywords
exosome, retinoic acid, Crabp1, RIP140, neuron, macrophage, inflammation
Figure 1
Figure 2
Figure 3
Figure 4
This is a list of supplementary files associated with this preprint. Click to download.
- S1.jpg
Figure S1. (a) FACS analysis of mouse plasma using RIP140 antibody. (b) FACS analysis of mouse CSF exosomes using RIP140 antibody.
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CURRENT STATUS: Under Review
Version 1
Posted 05 Apr, 2021
No community comments so far
Editorial decision: Minor Revision
On 18 Apr, 2021
Review #1 received
Received 13 Apr, 2021
Reviews received
Received 03 Apr, 2021
Reviewer #1 agreed
On 03 Apr, 2021
Reviewers invited
Invitations sent on 01 Apr, 2021
Editor assigned
On 30 Mar, 2021
Submission checks complete
On 30 Mar, 2021
Editor invited
On 30 Mar, 2021
First submitted
On 15 Feb, 2021
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Subject Areas
General Cell Biology & Physiology
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A new preprint design is coming!
We have improved readability, clarity, accessibility, and opportunities for engagement.
This preprint is under consideration at Cell Communication and Signaling. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Short report
Li-Na Wei
University of Minnesota Twin Cities Campus: University of Minnesota
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6376-8506
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 05 Apr, 2021
No community comments so far
Editorial decision: Minor Revision
On 18 Apr, 2021
Review #1 received
Received 13 Apr, 2021
Reviews received
Received 03 Apr, 2021
Reviewer #1 agreed
On 03 Apr, 2021
Reviewers invited
Invitations sent on 01 Apr, 2021
Editor assigned
On 30 Mar, 2021
Submission checks complete
On 30 Mar, 2021
Editor invited
On 30 Mar, 2021
First submitted
On 15 Feb, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
General Cell Biology & Physiology
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Intercellular communications are important for maintaining normal physiological processes. An important intercellular communication is mediated by the exchange of membrane-enclosed extracellular vesicles. Among various vesicles, exosomes can be detected in a wide variety of biological systems, but the regulation and biological implication of exosome secretion/uptake remains largely unclear.
Methods: Cellular retinoic acid (RA) binding protein 1 (Crabp1) knockout (CKO) mice were used for in vivo studies. Extracellular exosomes were monitored in CKO mice and relevant cell cultures including embryonic stem cell (CJ7), macrophage (Raw 264.7) and hippocampal cell (HT22) using Western blot and flow cytometry. Receptor Interacting Protein 140 (RIP140) was depleted by Crispr/Cas9-mediated gene editing. Anti-inflammatory maker was analyzed using qRT-PCR. Clinical relevance was accessed by mining multiple clinical datasets.
Results: This study uncovers Crabp1 as a negative regulator of exosome secretion from neurons. Specifically, RIP140, a pro-inflammatory regulator, can be transferred from neurons, via Crabp1-regulated exosome secretion, into macrophages to promote their inflammatory polarization. Consistently, CKO mice, defected in the negative control of exosome secretion, have significantly elevated RIP140-containing exosomes in their blood and cerebrospinal fluid, and exhibit an increased vulnerability to systemic inflammation. Clinical relevance of this pathway is supported by patients’ data of multiple inflammatory diseases. Further, the action of Crabp1 in regulating exosome secretion involves its ligand and is mediated by its downstream target, the MAPK signaling pathway.
Conclusions: This study presents the first evidence for the regulation of exosome secretion, which mediates intercellular communication, by RA-Crabp1 signaling. This novel mechanism can contribute to the control of systemic inflammation by transferring an inflammatory regulator, RIP140, between cells. This represents a new mechanism of vitamin A action that can modulate the homeostasis of system-wide innate immunity without involving gene regulation.
Figure 1
Figure 2
Figure 3
Figure 4
This is a list of supplementary files associated with this preprint. Click to download.
- S1.jpg
Figure S1. (a) FACS analysis of mouse plasma using RIP140 antibody. (b) FACS analysis of mouse CSF exosomes using RIP140 antibody.
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