TREM2, Driving the Microglial Polarization, Has a TLR4 Sensitivity Profile After Subarachnoid Hemorrhage

Abstract

Increasing evidence suggests that triggering receptor expressed on myeloid cells 2 (<i>TREM2</i>) is implicated in the pathophysiology of neuroinflammation. The aim here was to investigate the neuroprotective role of <i>TREM2</i> and its regulatory mechanism after subarachnoid hemorrhage (SAH). <i>TREM2</i> siRNA was administered to measure the detrimental role of <i>TREM2</i> in mediating microglial polarization <i>in vivo</i> and <i>in vitro</i> after experimental SAH. The relationship between Toll-like receptor 4 (<i>TLR4</i>) signaling and <i>TREM2</i> was further explored. The soluble <i>TREM2</i> from the cerebrospinal fluid (CSF) of patients with SAH was detected. The results showed that <i>TREM2</i> mainly located in the microglia and presented a markedly delayed elevation after SAH. <i>TREM2</i> knockdown triggered increased pro-inflammatory productions, aggravated microglial activities, and further exacerbated neurological dysfunction after SAH. Significantly, <i>TLR4</i> knockout increased the expression of <i>TREM2</i>, accompanied by ameliorated neuroinflammation and improved neurological function. Corresponding to different clinical Hunt-Hess grades, obviously enhanced accumulation of soluble <i>TREM2</i> was detected in the CSF of patients with SAH. <i>TREM2</i> played a pivotal role in mediating microglial polarization after SAH, and the neuroprotective effect of <i>TREM2</i> might be potentially suppressed by the hyperactive <i>TLR4</i> in the early phase of SAH. Pharmacological targeting of <i>TREM2</i> may be a promising strategy for SAH therapy.