Specific depletion of resident microglia in the early stage of stroke reduces cerebral ischemic damage
Specific depletion of resident microglia in the early stage of stroke reduces cerebral ischemic damage
Background
Ischemia can induce rapid activation of microglia in the brain. As key immunocompetent cells, reactive microglia play an important role in pathological development of ischemic stroke. However, the role of activated microglia during the development of ischemia remains controversial. Thus, we aimed to investigate the function of reactive microglia in the early stage of ischemic stroke.
Methods
A Rose Bengal photothrombosis model was applied to induce targeted ischemic stroke in mice. CX3CR1CreER:R26iDTR mice were used to specifically deplete resident microglia through intragastric administration of tamoxifen (Ta) and intraperitoneal injection of diphtheria toxin (DT). At day 3 after ischemic stroke, behavioral tests were performed. After that, mouse brains were collected for further histological analysis and detection of mRNA expression of inflammatory factors.
Results
The results showed that specific depletion of microglia resulted in a significant decrease in ischemic infarct volume and improved performance in motor ability 3 days after stroke. Microglial depletion caused a remarkable reduction in the densities of degenerating neurons and inducible nitric oxide synthase positive (iNOS+) cells. Importantly, depleting microglia induced a significant increase in the mRNA expression level of anti-inflammatory factors TGF-β1, Arg1, IL-10, IL-4, and Ym1 as well as a significant decline of pro-inflammatory factors TNF-α, iNOS, and IL-1β 3 days after stroke.
Conclusions
These results suggest that activated microglia is an important modulator of the brain’s inflammatory response in stroke, contributing to neurological deficit and infarct expansion. Modulation of the inflammatory response through the elimination of microglia at a precise time point may be a promising therapeutic approach for the treatment of cerebral ischemia.
Depletion, Function, Inflammation, Ischemia, Microglia
Li, T
40ebdcc3-b9c1-44ad-a766-9865b4e7790d
Zhao, J
66c4cee8-b5b5-4156-87ab-b263ca3bea4c
Xie, W
07e7c5ae-e7a0-45d4-b993-70e251ea6ef7
Yuan, W
c300a214-dcbe-46e9-830a-aa66ad41315a
Guo, J
576ac7ea-2d8a-41ee-b3db-bd2572576e14
Gan, W-B
a7537bd0-64fa-4cfd-9f34-2c8a48bda30c
Pang, S
83293a16-0717-4101-b5dd-e1b5bb69ffe6
Gomez-Nicola, D
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Zhang, S
fc3e6398-2c08-4cc4-ae15-4354d73978c3
23 March 2021
Li, T
40ebdcc3-b9c1-44ad-a766-9865b4e7790d
Zhao, J
66c4cee8-b5b5-4156-87ab-b263ca3bea4c
Xie, W
07e7c5ae-e7a0-45d4-b993-70e251ea6ef7
Yuan, W
c300a214-dcbe-46e9-830a-aa66ad41315a
Guo, J
576ac7ea-2d8a-41ee-b3db-bd2572576e14
Gan, W-B
a7537bd0-64fa-4cfd-9f34-2c8a48bda30c
Pang, S
83293a16-0717-4101-b5dd-e1b5bb69ffe6
Gomez-Nicola, D
0680aa66-9dee-47cf-a8d3-e39c988f85b5
Zhang, S
fc3e6398-2c08-4cc4-ae15-4354d73978c3
Li, T, Zhao, J, Xie, W, Yuan, W, Guo, J, Gan, W-B, Pang, S, Gomez-Nicola, D and Zhang, S
(2021)
Specific depletion of resident microglia in the early stage of stroke reduces cerebral ischemic damage.
Journal of Neuroinflammation, 18 (1), [81].
(doi:10.1186/s12974-021-02127-w).
Abstract
Background
Ischemia can induce rapid activation of microglia in the brain. As key immunocompetent cells, reactive microglia play an important role in pathological development of ischemic stroke. However, the role of activated microglia during the development of ischemia remains controversial. Thus, we aimed to investigate the function of reactive microglia in the early stage of ischemic stroke.
Methods
A Rose Bengal photothrombosis model was applied to induce targeted ischemic stroke in mice. CX3CR1CreER:R26iDTR mice were used to specifically deplete resident microglia through intragastric administration of tamoxifen (Ta) and intraperitoneal injection of diphtheria toxin (DT). At day 3 after ischemic stroke, behavioral tests were performed. After that, mouse brains were collected for further histological analysis and detection of mRNA expression of inflammatory factors.
Results
The results showed that specific depletion of microglia resulted in a significant decrease in ischemic infarct volume and improved performance in motor ability 3 days after stroke. Microglial depletion caused a remarkable reduction in the densities of degenerating neurons and inducible nitric oxide synthase positive (iNOS+) cells. Importantly, depleting microglia induced a significant increase in the mRNA expression level of anti-inflammatory factors TGF-β1, Arg1, IL-10, IL-4, and Ym1 as well as a significant decline of pro-inflammatory factors TNF-α, iNOS, and IL-1β 3 days after stroke.
Conclusions
These results suggest that activated microglia is an important modulator of the brain’s inflammatory response in stroke, contributing to neurological deficit and infarct expansion. Modulation of the inflammatory response through the elimination of microglia at a precise time point may be a promising therapeutic approach for the treatment of cerebral ischemia.
Text
Li_et_al-2021-Journal_of_Neuroinflammation
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More information
Accepted/In Press date: 11 March 2021
Published date: 23 March 2021
Additional Information:
Funding Information:
This work was supported by grants from the National Natural Science Foundation of China (No.31600831, 81771324), and the Fundamental Research Funds for the Central Universities (lzujbky-2018-102).
Publisher Copyright:
© 2021, The Author(s).
Keywords:
Depletion, Function, Inflammation, Ischemia, Microglia
Identifiers
Local EPrints ID: 448300
URI: http://eprints.soton.ac.uk/id/eprint/448300
ISSN: 1742-2094
PURE UUID: bb29b78d-528f-4660-a1cf-96bd05f49b06
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Date deposited: 19 Apr 2021 16:32
Last modified: 17 Mar 2024 03:22
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Contributors
Author:
T Li
Author:
J Zhao
Author:
W Xie
Author:
W Yuan
Author:
J Guo
Author:
W-B Gan
Author:
S Pang
Author:
S Zhang
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