TREM2 deficiency aggravates NLRP3 inflammasome activation and pyroptosis in MPTP-induced PD mice and LPS-induced BV2 cells

Abstract Background Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of PD. Triggering receptor expressed on myeloid cells 2(TREM2) confers strong neuroprotective effects in PD by regulating the phenotype of microglia. Recent studies suggest that TREM2 regulates high glucose-induced microglial inflammation through the NLRP3 signaling pathway. This study aimed to investigate the effect of TREM2 on NLRP3 inflammasome activation and neuroinflammation in PD. Method The AAV-TREM2-shRNA was injected into the substantia nigra of both sides of the mouse brain using a stereotactic injection method. The chronic PD mouse model was established by intraperitoneal injection of MPTP. Motor behavior test, immunohistochemistry of TREM2 and TH, immunohistochemistry and immunofluorescence Iba1, Western blot of NLRP3 inflammasome and its downstream inflammatory factors IL−1β and IL−18, and the key pyroptosis factors GSDMD and GSDMD-N were performed to explore the effect of TREM2 on NLRP3 inflammasome and neuroinflammation. In vitro experiment, Lentivirus was used to interfere with the expression of TREM2 in BV2 microglia, then LPS and ATP were used to stimulate inflammation to construct a cellular inflammation model. The expression differences of NLRP3 inflammasome and its components were detected by qPCR and western blot. Result In vivo, TREM2 expression was decreased, dopaminergic neuron loss was increased, and motor function was decreased, indicating that TREM2 knockdown and PD mouse models were successfully constructed. After TREM2 knockdown, the number of activated microglia was significantly increased, and the expression of cleaved caspase−1, NLRP3 inflammasome, IL−1β, GSDMD, GSDMD-N was increased. In vitro, TREM2 knockdown aggravated the inflammatory response of BV2 cells stimulated by LPS and promoted the activation of NLRP3 inflammasome through the NF-κB pathway. In addition, TREM2 knockdown also promoted the expression of TLRP4/MyD88, an upstream factor of the NF-κB pathway. Discussion Our in vivo and in vitro data showed that TREM2 knockdown promoted NLRP3 inflammasome activation and downstream inflammatory response, promoted pyroptosis, and aggravated dopaminergic neuron loss, which extends previous findings and support the notion that TREM2 acts as an important anti-inflammatory factor to ameliorate neuroinflammation in PD.