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TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus

BACKGROUND: Diabetes mellitus (DM) and chronic cerebral hypoperfusion(CCH)are both risk factors for cognitive impairment. However, whether DM and CCH can synergistically promote cognitive impairment and the related pathological mechanisms remain unknown. METHODS: To investigate the effect of DM and...

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Autores principales: Zhang, Jiawei, Liu, Yu, Zheng, Yaling, Luo, Yan, Du, Yu, Zhao, Yao, Guan, Jian, Zhang, Xiaojie, Fu, Jianliang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942413/
https://www.ncbi.nlm.nih.gov/pubmed/31900229
http://dx.doi.org/10.1186/s12974-019-1688-9
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author Zhang, Jiawei
Liu, Yu
Zheng, Yaling
Luo, Yan
Du, Yu
Zhao, Yao
Guan, Jian
Zhang, Xiaojie
Fu, Jianliang
author_facet Zhang, Jiawei
Liu, Yu
Zheng, Yaling
Luo, Yan
Du, Yu
Zhao, Yao
Guan, Jian
Zhang, Xiaojie
Fu, Jianliang
author_sort Zhang, Jiawei
collection PubMed
description BACKGROUND: Diabetes mellitus (DM) and chronic cerebral hypoperfusion(CCH)are both risk factors for cognitive impairment. However, whether DM and CCH can synergistically promote cognitive impairment and the related pathological mechanisms remain unknown. METHODS: To investigate the effect of DM and CCH on cognitive function, rats fed with high-fat diet (HFD) and injected with low-dose streptozotocin (STZ) followed by bilateral common carotid artery occlusion (BCCAO) were induced to mimic DM and CCH in vivo and mouse BV2 microglial cells were exposed to hypoxia and/or high glucose to mimic CCH complicated with DM pathologies in vitro. To further explore the underlying mechanism, TREM-2-specific small interfering RNA and TREM-2 overexpression lentivirus were used to knock out and overexpress TREM-2, respectively. RESULTS: Cognitive deficits, neuronal cell death, neuroinflammation with microglial activation, and TREM-2-MAPK signaling were enhanced when DM was superimposed on CCH both in vivo and in vitro. Manipulating TREM-2 expression levels markedly regulated the p38 MAPK signaling and the inflammatory response in vitro. TREM-2 knockout intensified while TREM-2 overexpression suppressed the p38 MAPK signaling and subsequent pro-inflammatory mediator production under high glucose and hypoxia condition. CONCLUSIONS: These results suggest that TREM-2 negatively regulates p38 MAPK-mediated inflammatory response when DM was synergistically superimposed on CCH and highlight the importance of TREM-2 as a potential target of immune regulation in DM and CCH.
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spelling pubmed-69424132020-01-07 TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus Zhang, Jiawei Liu, Yu Zheng, Yaling Luo, Yan Du, Yu Zhao, Yao Guan, Jian Zhang, Xiaojie Fu, Jianliang J Neuroinflammation Research BACKGROUND: Diabetes mellitus (DM) and chronic cerebral hypoperfusion(CCH)are both risk factors for cognitive impairment. However, whether DM and CCH can synergistically promote cognitive impairment and the related pathological mechanisms remain unknown. METHODS: To investigate the effect of DM and CCH on cognitive function, rats fed with high-fat diet (HFD) and injected with low-dose streptozotocin (STZ) followed by bilateral common carotid artery occlusion (BCCAO) were induced to mimic DM and CCH in vivo and mouse BV2 microglial cells were exposed to hypoxia and/or high glucose to mimic CCH complicated with DM pathologies in vitro. To further explore the underlying mechanism, TREM-2-specific small interfering RNA and TREM-2 overexpression lentivirus were used to knock out and overexpress TREM-2, respectively. RESULTS: Cognitive deficits, neuronal cell death, neuroinflammation with microglial activation, and TREM-2-MAPK signaling were enhanced when DM was superimposed on CCH both in vivo and in vitro. Manipulating TREM-2 expression levels markedly regulated the p38 MAPK signaling and the inflammatory response in vitro. TREM-2 knockout intensified while TREM-2 overexpression suppressed the p38 MAPK signaling and subsequent pro-inflammatory mediator production under high glucose and hypoxia condition. CONCLUSIONS: These results suggest that TREM-2 negatively regulates p38 MAPK-mediated inflammatory response when DM was synergistically superimposed on CCH and highlight the importance of TREM-2 as a potential target of immune regulation in DM and CCH. BioMed Central 2020-01-03 /pmc/articles/PMC6942413/ /pubmed/31900229 http://dx.doi.org/10.1186/s12974-019-1688-9 Text en © The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Zhang, Jiawei
Liu, Yu
Zheng, Yaling
Luo, Yan
Du, Yu
Zhao, Yao
Guan, Jian
Zhang, Xiaojie
Fu, Jianliang
TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus
title TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus
title_full TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus
title_fullStr TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus
title_full_unstemmed TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus
title_short TREM-2-p38 MAPK signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus
title_sort trem-2-p38 mapk signaling regulates neuroinflammation during chronic cerebral hypoperfusion combined with diabetes mellitus
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6942413/
https://www.ncbi.nlm.nih.gov/pubmed/31900229
http://dx.doi.org/10.1186/s12974-019-1688-9
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