Soluble TREM2 ameliorates pathological phenotypes in ischemic stroke models via modulating neuronal and microglial functions.

Although the neuroprotective effects of triggering receptor expressed on myeloid cell 2 (TREM2) upregulation after ischemic stroke has been demonstrated, the level change and effect of soluble TREM2 (sTREM2) derived from proteolytic cleavage of the TREM2 extracellular domain in ischemic stroke remain unknown. In our study, the level and function of sTREM2 were detected in neuron-microglia co-cultures subjected to oxygen glucose deprivation (OGD) and in the ischemic striatum of C57BL/6 J mice in a transient middle cerebral artery occlusion (tMCAO) model. sTREM2's effect on neuronal nitric oxide synthase (nNOS)-postsynaptic density protein-95 (PSD-95) interaction was determined by co-immunoprecipitation. The microglial-activated morphology in the striatum was identified by immunohistochemistry. Quantitative real-time polymerase chain reactionwas used to detect the transcriptional levels of TREM2, shorter variant TREM2, insulin-like growth factor 1, interleukin (IL)-4, and IL-13. Levels of sTREM2, generated through the cleavage of full-length TREM2 at the His157-Ser158 peptide bond, declined after OGD and tMCAO. sTREM2 reduced neuronal death after OGD and alleviated brain infarction and neurological deficits after tMCAO by disrupting the nNOS-PSD-95 interaction, promoting microglial activation, and increasing the expression of some cytokines associated with microglial polarization towards an anti-inflammatory phenotype. To the best of our knowledge, this is the first study to suggest that sTREM2 protects against transient cerebral ischemia.