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Tytuł:
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PLXNA2 knockdown promotes M2 microglia polarization through mTOR/STAT3 signaling to improve functional recovery in rats after cerebral ischemia/reperfusion injury.
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Autorzy:
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Li S; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Hua X; Department of Traumatology and Orthopedics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
Zheng M; Department of Traumatology and Orthopedics, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
Wu J; Center of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
Ma Z; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Xing X; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Ma J; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Zhang J; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Shan C; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Center of Rehabilitation Medicine, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China; Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai 201203, China.
Xu J; School of Rehabilitation Science, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Engineering Research Center of Traditional Chinese Medicine Intelligent Rehabilitation, Ministry of Education, Shanghai 201203, China. Electronic address: .
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Źródło:
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Experimental neurology [Exp Neurol] 2021 Dec; Vol. 346, pp. 113854. Date of Electronic Publication: 2021 Aug 30.
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Typ publikacji:
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Journal Article; Research Support, Non-U.S. Gov't
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Język:
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English
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Imprint Name(s):
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Publication: Orlando Fl : Academic Press
Original Publication: New York.
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MeSH Terms:
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Brain Ischemia/*metabolism
Microglia/*metabolism
Nerve Tissue Proteins/*deficiency
Receptors, Cell Surface/*deficiency
Reperfusion Injury/*metabolism
STAT3 Transcription Factor/*metabolism
TOR Serine-Threonine Kinases/*metabolism
Animals ; Brain Ischemia/genetics ; Brain Ischemia/pathology ; Gait Analysis/methods ; Gene Knockdown Techniques/methods ; Male ; Maze Learning/physiology ; Microglia/pathology ; Nerve Tissue Proteins/antagonists & inhibitors ; Nerve Tissue Proteins/genetics ; Rats ; Rats, Sprague-Dawley ; Receptors, Cell Surface/antagonists & inhibitors ; Receptors, Cell Surface/genetics ; Recovery of Function/physiology ; Reperfusion Injury/genetics ; Reperfusion Injury/pathology ; STAT3 Transcription Factor/antagonists & inhibitors ; STAT3 Transcription Factor/genetics ; TOR Serine-Threonine Kinases/antagonists & inhibitors ; TOR Serine-Threonine Kinases/genetics
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Contributed Indexing:
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Keywords: Cognitive; Microglia polarization; Motor; PLXNA2; STAT3; mTOR
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Substance Nomenclature:
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0 (Nerve Tissue Proteins)
0 (Plxna2 protein, rat)
0 (Receptors, Cell Surface)
0 (STAT3 Transcription Factor)
0 (Stat3 protein, rat)
EC 2.7.1.1 (mTOR protein, rat)
EC 2.7.11.1 (TOR Serine-Threonine Kinases)
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Entry Date(s):
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Date Created: 20210902 Date Completed: 20211220 Latest Revision: 20211220
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Update Code:
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20240105
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DOI:
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10.1016/j.expneurol.2021.113854
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PMID:
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34474008
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Ischemic stroke is an acute cerebrovascular disease characterized by high mortality, morbidity and disability rates. Ischemia/reperfusion is a critical pathophysiological basis of motor and cognitive dysfunction caused by ischemic stroke. Microglia, innate immune cells of the central nervous system, mediate the neuroinflammatory response to ischemia/reperfusion. PlexinA2 (PLXNA2) plays an important role in the regulation of neuronal axon guidance, the immune response and angiogenesis. However, it is not clear whether PLXNA2 regulates microglia polarization in ischemic stroke or the underlying mechanism. In the present study, we investigated the role of PLXNA2 in rats with middle cerebral artery occlusion/reperfusion (MCAO/R) and BV2 microglia cells with oxygen and glucose deprivation/reoxygenation (OGD/R). A battery of behavioral tests, including the beam balance test, forelimb placement test, foot fault test, cylinder test, CatWalk gait analysis and Morris water maze test were performed to evaluate sensorimotor function, locomotor activity and cognitive ability. The expression of M1/M2-specific markers in the ischemic penumbra and BV2 microglia cells was detected using immunofluorescence staining, quantitative real-time PCR analysis and Western blot analysis. Our study showed that PLXNA2 knockdown accelerated the recovery of motor function and cognitive ability after MCAO/R. In addition, PLXNA2 knockdown restrained proinflammatory cytokine release and promoted anti-inflammatory cytokine release, and the mammalian target of rapamycin (mTOR)/signal transducer and activator of transcription 3 (STAT3) pathway was involved in PLXNA2 regulated microglia polarization. Taken together, our results indicate that PLXNA2 knockdown reduces neuroinflammation by switching the microglia phenotype from M1 to M2 in the ischemic penumbra of MCAO/R-injured rats, which may be due to the inhibition of mTOR/STAT3 signaling. Treatments targeting PLXNA2 may be a promising therapeutic strategy for ischemic stroke.
(Copyright © 2021 Elsevier Inc. All rights reserved.)
