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.
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Research
Min Liao
wenzhou medical university
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6141-1626
License:
This work is licensed under a CC BY 4.0 License. Read Full License
Background
Proinflammatory microglia rely predominantly on glycolysis to maintain cytokine production during an inflammatory response. However, during ischemia, where glucose supply is low, inducible nitric oxide synthase (iNOS) production remains high accompanied by an increase in monocarboxylate transporter 1 (MCT1) expression. In this study, we explored whether there is a link between iNOS and MCT1 expressions, and whether pyruvate can act as an energy source to sustain the M1 phenotype.
Methods
Using a mouse model with laser-induced brain ischemia and cell culture with low-glucose treatment, we examined responses from microglia.
Results
The expressions of iNOS and MCT1, as well as arginase-1 (ARG1), were increased in the brain of the ischemic mouse model. In the BV2 microglial cell line and primary microglia treated under low glucose condition, iNOS and MCT1 also increased, while ARG1 decreased. The addition of pyruvate under low-glucose or lipopolysaccharide (LPS) treatment enhanced iNOS and MCT1 expressions compared with groups without pyruvate. MCT1 knockdown resulted in decreased iNOS while MCT1 overexpression increased iNOS. Furthermore, inhibitor of nuclear factor-kappaB (NF-κB) reduced both iNOS and MCT1.
Conclusion
Our data suggested that after proinflammatory microglial polarization, MCT1 is upregulated through the NF-κB signaling pathway, which leads to iNOS production. We speculate that microglia may continuously pick up monocarboxylates such as pyruvate through MCT1 to sustain the M1 phenotype.
Keywords
Microglia, INOS, MCT1, Pyruvate, Ischemia, Low glucose condition
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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
Min Liao
wenzhou medical university
Corresponding Author
ORCiD: https://orcid.org/0000-0002-6141-1626
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 08 Jun, 2020
No community comments so far
Editor assigned
On 04 Jun, 2020
First submitted
On 03 Jun, 2020
Submission checks complete
On 03 Jun, 2020
Editor invited
On 03 Jun, 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
Proinflammatory microglia rely predominantly on glycolysis to maintain cytokine production during an inflammatory response. However, during ischemia, where glucose supply is low, inducible nitric oxide synthase (iNOS) production remains high accompanied by an increase in monocarboxylate transporter 1 (MCT1) expression. In this study, we explored whether there is a link between iNOS and MCT1 expressions, and whether pyruvate can act as an energy source to sustain the M1 phenotype.
Methods
Using a mouse model with laser-induced brain ischemia and cell culture with low-glucose treatment, we examined responses from microglia.
Results
The expressions of iNOS and MCT1, as well as arginase-1 (ARG1), were increased in the brain of the ischemic mouse model. In the BV2 microglial cell line and primary microglia treated under low glucose condition, iNOS and MCT1 also increased, while ARG1 decreased. The addition of pyruvate under low-glucose or lipopolysaccharide (LPS) treatment enhanced iNOS and MCT1 expressions compared with groups without pyruvate. MCT1 knockdown resulted in decreased iNOS while MCT1 overexpression increased iNOS. Furthermore, inhibitor of nuclear factor-kappaB (NF-κB) reduced both iNOS and MCT1.
Conclusion
Our data suggested that after proinflammatory microglial polarization, MCT1 is upregulated through the NF-κB signaling pathway, which leads to iNOS production. We speculate that microglia may continuously pick up monocarboxylates such as pyruvate through MCT1 to sustain the M1 phenotype.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
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