Triggering Receptor Expressed on Myeloid Cells 2, a Novel Regulator of Immunocyte Phenotypes, Confers Neuroprotection by Relieving Neuroinflammation

Abstract

Background Microglia can not only detrimentally augment secondary injury but also potentially promote recovery. However, the mechanism underlying the regulation of microglial phenotypes after stroke remains unclear. Methods Mice were subjected to middle cerebral artery occlusion for 60 min. At 3 days after reperfusion, the effects of activation and suppression of triggering receptor expressed on myeloid cells 2 on immunocyte phenotypes (n = 5), neurobehavioral scores (n = 7), infarct volumes (n = 8), and neuronal apoptosis (n = 7) were analyzed. In vitro, cultured microglia were exposed to oxygen–glucose deprivation for 4 h. Inflammatory cytokines, cellular viability (n = 8), neuronal apoptosis (n = 7), and triggering receptor expressed on myeloid cells 2 expression (n = 5) were evaluated in the presence or absence of triggering receptor expressed on myeloid cell-specific small interfering RNA or triggering receptor expressed on myeloid cells 2 overexpression lentivirus. Results Triggering receptor expressed on myeloid cells 2 expression in the ischemic penumbra peaked at 3 days after ischemia–reperfusion injury (4.4 ± 0.1-fold, P = 0.0004) and was enhanced in interleukin-4/interleukin-13–treated microglia in vitro (1.7 ± 0.2-fold, P = 0.0119). After oxygen–glucose deprivation, triggering receptor expressed on myeloid cells 2 conferred neuroprotection by regulating the phenotypic conversion of microglia and inflammatory cytokine release. Intraperitoneal administration of triggering receptor expressed on myeloid cells 2 agonist heat shock protein 60 or unilateral delivery of a recombinant triggering receptor expressed on myeloid cells 2 lentivirus into the cerebral ventricle induced a significant neuroprotective effect in mice (apoptotic neurons decreased to 31.3 ± 7.6%; infarct volume decreased to 44.9 ± 5.3%). All values are presented as the mean ± SD. Conclusions Activation or up-regulation of triggering receptor expressed on myeloid cells 2 promoted the phenotypic conversion of microglia and decreased the number of apoptotic neurons. Our study suggests that triggering receptor expressed on myeloid cells 2 is a novel regulator of microglial phenotypes and may be a potential therapeutic target for stroke.

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.…”

Triggering Receptor Expressed on Myeloid Cells-2 (TREM2) Inhibits Steroidogenesis in Adrenocortical Cell by Macrophage-derived Exosomes in Lipopolysaccharide-induced Septic Shock

“…TREM2 is extensively studied in central chronic degenerative diseases especially Alzheimer's disease, and plays an important regulatory role in local or systemic in ammatory disorders [19,21,34]. Genetic or functional interventions of TREM2 result in reduced accumulation of surrounding plaques, impaired microglial phagocytosis as well as marked adjacent neuronal dystrophy [20,35,36].…”

“…Prior studies have con rmed that TREM2 played a protective role in the host defense response to polymicrobial sepsis by enhanced clearance of microbes, and activation of TREM2 promoted microglial switching from the detrimental M1 phenotype to the bene cial M2 phenotype in a mouse model of middle cerebral artery occlusion [19,21]. However, the role of TREM2 when encountered with an acute in ammatory challenge is still controversial.…”

“…Studies con rmed that TREM2 was crucial to maintain microgliosis in response to pathological processes of Alzheimer's disease (AD) and other neurodegenerative diseases [16][17][18]. Recently, some studies also showed that TREM2 played an important regulatory role in local or systemic in ammatory disorders [19][20][21]. Despite the reported function of TREM2 in pathological conditions in the CNS, whether TREM2 interacts with the neuroendocrine system and how TREM2 impacts progress of septic shock remains unexplored.…”