Mol Brain. 2017 Jun 7;10(1):20 

TREM2 protects against cerebral ischemia/reperfusion injury

Yamei Tang


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.To investigate the role of TREM2 during ischemic stroke, we first examined cultured primary microglia cells that had been subjected to OGDR. The results of quantitative real-time PCR (Fig. 1a) and western blotting (Fig. 1b and c) analyses indicated that OGDR significantly enhanced microglial TREM2 expression in a time-dependent manner at both transcriptional and post-transcriptional levels, with a peak expression of TREM2 12h after reoxygenation. We then examined the mRNA (Fig. 1d) and protein (Fig. 1e and f) expression levels of TREM2 after reperfusion in mice subjected to MCAO and found that TREM2 mRNA and protein were markedly increased in the ischemic cerebral hemisphere (ischemic core and penumbra), with a peak expression 7 days after the MCAO. These results provided in vitro and in vivo evidence that TREM2 was involved in ischemic stroke.Adult 6- to 8-week-old male C57BL/6J mice, weighing 20–25g, were housed under diurnal lighting conditions with 12h of light (lights on at 7:00 AM) and allowed access to food and water ad libitum. The MCAO model used was previously developed and described [39, 40]. Briefly, after mice were deeply anesthetized with chloral hydrate (200mg/kg, intraperitoneal injection), their fur and skin were disinfected with povidone-iodine (Betadine, Purdue Frederich Company, Norwalk, CT, USA). A midline neck incision was made, and the soft tissues were retracted. Thecommon carotid artery, bifurcation of the internal common carotid artery (ICA), and external common carotid artery (ECA) were carefully dissected. The ECA was temporarily occluded using a 5-0 silk suture. The ICA was clipped using reverse-action tweezers to minimize bleeding. A small hole was cut into the ECA for the insertion of a silicone-coated filament (Beijing Cinontech Co.Ltd, Beijing, China) into the ICA. The suture was tightly tied around the monofilament to prevent bleeding, and the reverse-action tweezers were removed. After 90 min, the suture was removed for reperfusion, and the wound and skin were closed. The body temperature of the mice was maintained between 37.0°C and 37.5°C with a heating pad during surgery. For sham operations, all procedures were identical except that the occluding monofilament was not inserted. There was no significant difference in the average body weight or temperature between groups [41].We thank Xuecheng Qiu for discussion and for help on analyzing the data.Electronic supplementary materialThe online version of this article (doi:10.1186/s13041-017-0296-9) contains supplementary material, which is available to authorized users.
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