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Mer regulates microglial M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury
Jianmin Zhang
Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3184-1502
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Background: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial activation and neuroinflammation are key cellular events following TBI, but the regulatory and functional mechanisms are still not well understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, regulates multiple features of microglial physiology. However, its function in regulating the innate immune response and microglial M1/M2 polarization in TBI has not been addressed. The present study aimed to evaluate the role of Mer in regulating microglial M1/M2 polarization and neuroinflammation following TBI.
Methods: The controlled cortical impact (CCI) mouse model was established. Mer siRNA was intracerebroventricularly administered and recombinant protein S (PS) was intravenously applied for intervention. The neurobehavioral assessments, RT-PCR, Western blot, immunohistochemistry and confocal microscopy analysis, Nissl and Fluoro-Jade B staining, brain water content measurement, and contusion volume assessment were performed.
Results: Mer is upregulated and regulates microglial M1/M2 polarization and neuroinflammation in the acute stage of TBI. Mechanistically, Mer activates the signal transducer and activator of transcription 1 (STAT1)/suppressor of cytokine signaling 1/3 (SOCS1/3) pathway. Inhibition of Mer markedly decreases microglial M2 polarization while increases M1 polarization, which exacerbates the secondary brain damage and sensorimotor deficits after TBI. Recombinant PS exerts beneficial effects in TBI mice through Mer activation.
Conclusions: Mer is an important regulator of microglial M1/M2 polarization and neuroinflammation, and may be considered as a potential target for therapeutic intervention in TBI.
Keywords
Mer, Microglia, M1/M2 polarization, neuroinflammation, TBI
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CURRENT STATUS: Under Revision
Version 1
Posted 22 May, 2020
No community comments so far
Review #3 received
Received 30 Jun, 2020
Editorial decision: Major Revision
On 30 Jun, 2020
Review #2 received
Received 09 Jun, 2020
Review #1 received
Received 09 Jun, 2020
Reviewer #3 agreed
On 26 May, 2020
Reviewer #1 agreed
On 25 May, 2020
Reviewer #2 agreed
On 25 May, 2020
Reviewers invited
Invitations sent on 23 May, 2020
Editor assigned
On 18 May, 2020
First submitted
On 17 May, 2020
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On 17 May, 2020
Editor invited
On 17 May, 2020
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Subject Areas
Neurobiology of Disease
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This preprint is under consideration at Journal of Neuroinflammation. 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
Research
Mer regulates microglial M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury
Jianmin Zhang
Department of Neurosurgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University
Corresponding Author
ORCiD: https://orcid.org/0000-0002-3184-1502
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 Revision
Version 1
Posted 22 May, 2020
No community comments so far
Review #3 received
Received 30 Jun, 2020
Editorial decision: Major Revision
On 30 Jun, 2020
Review #2 received
Received 09 Jun, 2020
Review #1 received
Received 09 Jun, 2020
Reviewer #3 agreed
On 26 May, 2020
Reviewer #1 agreed
On 25 May, 2020
Reviewer #2 agreed
On 25 May, 2020
Reviewers invited
Invitations sent on 23 May, 2020
Editor assigned
On 18 May, 2020
First submitted
On 17 May, 2020
Submission checks complete
On 17 May, 2020
Editor invited
On 17 May, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
Subject Areas
Neurobiology of Disease
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background: Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial activation and neuroinflammation are key cellular events following TBI, but the regulatory and functional mechanisms are still not well understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), a member of the Tyro-Axl-Mer (TAM) family of receptor tyrosine kinases, regulates multiple features of microglial physiology. However, its function in regulating the innate immune response and microglial M1/M2 polarization in TBI has not been addressed. The present study aimed to evaluate the role of Mer in regulating microglial M1/M2 polarization and neuroinflammation following TBI.
Methods: The controlled cortical impact (CCI) mouse model was established. Mer siRNA was intracerebroventricularly administered and recombinant protein S (PS) was intravenously applied for intervention. The neurobehavioral assessments, RT-PCR, Western blot, immunohistochemistry and confocal microscopy analysis, Nissl and Fluoro-Jade B staining, brain water content measurement, and contusion volume assessment were performed.
Results: Mer is upregulated and regulates microglial M1/M2 polarization and neuroinflammation in the acute stage of TBI. Mechanistically, Mer activates the signal transducer and activator of transcription 1 (STAT1)/suppressor of cytokine signaling 1/3 (SOCS1/3) pathway. Inhibition of Mer markedly decreases microglial M2 polarization while increases M1 polarization, which exacerbates the secondary brain damage and sensorimotor deficits after TBI. Recombinant PS exerts beneficial effects in TBI mice through Mer activation.
Conclusions: Mer is an important regulator of microglial M1/M2 polarization and neuroinflammation, and may be considered as a potential target for therapeutic intervention in TBI.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the manuscript can be downloaded and accessed as a PDF.