TREM2 protects against cerebral ischemia/reperfusion injury

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.

Shared genes between Alzheimer’s disease and ischemic stroke

“…Mutation of rare variants in TREM2 confers a substantial increase in AD risk, which has been experimentally proved . TREM2 has been indicated to be upregulated and participate in ischemic brain damage by modulating microglial phenotypes despite conflicting findings . Here, TREM2 was shared by AD and IS with individual P = 0.0015 and P = 0.0095, respectively.…”

“…94,95 TREM2 has been indicated to be upregulated and participate in ischemic brain damage by modulating microglial phenotypes despite conflicting findings. [96][97][98][99][100] Here, TREM2 was shared by AD and IS with individual P = 0.0015 and P = 0.0095, respectively. Since rare variants (MAF < 0.01) were excluded from the GWAS panels of both AD and IS, we assumed that the true joint association signal of TREM2 with AD and IS might be stronger than we observed.…”

Immune responses in stroke: how the immune system contributes to damage and healing after stroke and how this knowledge could be translated to better cures?

“…Findings from several studies already suggest a potential anti‐inflammatory role of microglial cells that may contribute to neuroprotection after stroke. Microglial expression of P2X7 receptor, triggering receptors expressed on myeloid cells (TREM2), ST2/IL‐33, and B‐cell activating factor could be involved in limiting ischaemic neuronal injury. Activation of these microglial‐dependent signalling factors results in the release of anti‐inflammatory cytokines, such as IL‐10, IL‐4 and transforming growth factor‐ β , which may contribute to neuronal survival .…”

“…Microglial expression of P2X7 receptor, triggering receptors expressed on myeloid cells (TREM2), ST2/IL‐33, and B‐cell activating factor could be involved in limiting ischaemic neuronal injury. Activation of these microglial‐dependent signalling factors results in the release of anti‐inflammatory cytokines, such as IL‐10, IL‐4 and transforming growth factor‐ β , which may contribute to neuronal survival . Microglial secretion of these neuroprotective factors, as well as phagocytic activity, are characteristic of the protective ‘M2’ phenotype of myeloid cells .…”

MicroRNA-155-5p suppresses cardiomyocytes apoptosis induced by hypoxia/reoxygenation via targeting fos-related antigen 2

“…Myocardial I/R injury accelerate both cardiomyocyte apoptosis and cardiac fibrosis, which finally trigger heart failure [19]. Consequently, intensive investigation the potential molecular mechanisms are crucial for development effective treatment option for myocardial I/R injury.…”