TREM2 protects against cerebral ischemia/reperfusion injury

Rong Wu,Long-Jun Wu,Pengfei Xu,Xiangpen Li,Xiaolong Huang,Likui Huang,Yamei Tang,Jingru Jiang,Jinping Cheng

doi:10.1186/s13041-017-0296-9

Abstract

Although post-ischemic inflammation induced by the innate immune response is considered an essential step in the progression of cerebral ischemia injury, the role of triggering receptor expressed on myeloid cells 2 (TREM2) in the pathogenesis of ischemic stroke remains to be elucidated. Here, we found that the transcriptional and post-transcriptional levels of TREM2 were increased in cultured primary microglia after oxygen-glucose deprivation and reoxygenation and in the ischemic penumbra of the cerebral cortex after middle cerebral artery occlusion (MCAO) and reperfusion in mice. TREM2 was mainly expressed in microglia, but not in astrocytes, neurons, or oligodendrocytes in mice subjected to MCAO. Manipulating TREM2 expression levels in vitro and in vivo significantly regulated the production of pro- and anti-inflammatory mediators after ischemic stroke. TREM2 overexpression markedly suppressed the inflammatory response and neuronal apoptosis. By contrast, TREM2 gene silencing intensified the inflammatory response, increased neuronal apoptosis and infarct volume, and further exacerbated neurological dysfunction. Our study demonstrated that TREM2 protects against cerebral ischemia/reperfusion injury through the aspect of post-ischemic inflammatory response and neuronal apoptosis. Pharmacological targeting of TREM2 to suppress the inflammatory response may provide a new approach for developing therapeutic strategies in the treatment of ischemic stroke and other cerebrovascular diseases.

Highlights

Stroke is the leading cause of disability and mortality worldwide
Increased expression of triggering receptor expressed on myeloid cells 2 (TREM2) after ischemic stroke in vitro and in vivo To investigate the role of TREM2 during ischemic stroke, we first examined cultured primary microglia cells that had been subjected to oxygen-glucose deprivation and reoxygenation (OGDR)
Up-regulated TREM2 is localized in microglia in middle cerebral artery occlusion (MCAO) mice We determined the type of cell responsible for the increased cerebral TREM2 after ischemia

Summary

Introduction

Stroke is the leading cause of disability and mortality worldwide. Ischemic stroke is a common vascular disease in the central nervous system (CNS) [2]. Acute cerebral ischemia elicits an immune response that leads to a cascade of events culminating in neuronal death and injury to supportive structures in the brain [3]. Pharmacological thrombolysis is limited by its Microglia, considered the macrophages of the CNS, are involved in chronic inflammation [7] and are activated early after ischemia, preceding the invasion of blood-borne immune cells [8]. Microglia can produce pro-inflammatory mediators and neurotoxic compounds, such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, reactive oxygen species, nitric oxide, and prostaglandin E2 [9, 10], which are important determinants of neuronal death in cerebral ischemia.

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