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

Pengfei Xu,Gelin Xu,Hongquan Guo,Rui Sun,Yi Xie,Xiaohao Zhang,Xiaolei Shi,Jingjing Chen,Ye Hong,Yunzi Li,Qian Liu,Xinfeng Liu

doi:10.1038/s41419-019-1777-9

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-κB, 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.

Highlights

In the central nervous system (CNS), microglia serve as the resident mononuclear phagocytes and are key cellular mediators participated in both acute and chronic neuroinflammatory responses[1]
In this study, using mice middle cerebral artery occlusion (MCAO) model and microglia oxygenglucose deprivation (OGD) model, we examined whether microglial Triggering receptor expressed on myeloid cells (TREM)-1 regulates neuroinflammation following brain ischemic injury and whether this involvement is though interaction with spleen tyrosine kinase (SYK)
Ischemic cerebral injuries lead to permanent damages to the brain lacking blood flow, whose progression involve an essential step of post-ischemic inflammation, and may affect physical functioning and cognition

Summary

Introduction

In the central nervous system (CNS), microglia serve as the resident mononuclear phagocytes and are key cellular mediators participated in both acute and chronic neuroinflammatory responses[1]. Neuroinflammation plays a dual role in cerebral ischemic cascade[2]. It is an essential tool to eliminate dead cells and necrotic debris caused by Triggering receptor expressed on myeloid cells 1 1), a transmembrane immune receptor, is expressed on the surface of phagocytic cells, acting as a potent amplifier of inflammation[7,8,9,10]. TREM-1 can recruit spleen tyrosine kinase (SYK)[9], which has been regarded as a launching point of inflammation after ischemic stroke[11]. Blockade of Official journal of the Cell Death Differentiation Association

Methods

Results

Conclusion