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Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke.


ABSTRACT: Neuroinflammation is initiated in response to ischemic stroke, generally with the hallmarks of microglial activation and collateral brain injury contributed by robust inflammatory effects. Triggering receptor expressed on myeloid cells (TREM)-1, an amplifier of the innate immune response, is a critical regulator of inflammation. This study identified that microglial TREM-1 expression was upregulated following cerebral ischemic injury. After pharmacologic inhibition of TREM-1 with synthetic peptide LP17, ischemia-induced infarction and neuronal injury were substantially alleviated. Moreover, blockade of TREM-1 can potentiate cellular proliferation and synaptic plasticity in hippocampus, resulting in long-term functional improvement. Microglial M1 polarization and neutrophil recruitment were remarkably abrogated as mRNA levels of M1 markers, chemokines, and protein levels of myeloperoxidase and intracellular adhesion molecule-1 (ICAM-1) were decreased by LP17. Mechanistically, both in vivo and in vitro, we delineated that TREM-1 can activate downstream pro-inflammatory pathways, CARD9/NF-?B, and NLRP3/caspase-1, through interacting with spleen tyrosine kinase (SYK). In addition, TREM-1-induced SYK initiation was responsible for microglial pyroptosis by elevating levels of gasdermin D (GSDMD), N-terminal fragment of GSDMD (GSDMD-N), and forming GSDMD pores, which can facilitate the release of intracellular inflammatory factors, in microglia. In summary, microglial TREM-1 receptor yielded post-stroke neuroinflammatory damage via associating with SYK.

SUBMITTER: Xu P 

PROVIDER: S-EPMC6642102 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Microglial TREM-1 receptor mediates neuroinflammatory injury via interaction with SYK in experimental ischemic stroke.

Xu Pengfei P   Zhang Xiaohao X   Liu Qian Q   Xie Yi Y   Shi Xiaolei X   Chen Jingjing J   Li Yunzi Y   Guo Hongquan H   Sun Rui R   Hong Ye Y   Liu Xinfeng X   Xu Gelin G  

Cell death & disease 20190719 8


Neuroinflammation is initiated in response to ischemic stroke, generally with the hallmarks of microglial activation and collateral brain injury contributed by robust inflammatory effects. Triggering receptor expressed on myeloid cells (TREM)-1, an amplifier of the innate immune response, is a critical regulator of inflammation. This study identified that microglial TREM-1 expression was upregulated following cerebral ischemic injury. After pharmacologic inhibition of TREM-1 with synthetic pepti  ...[more]

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