Microglial NLRP3 inflammasome activation mediates diabetes-induced depression-like behavior of mice via triggering neuroinflammation

Background: Abundant evidence suggests that people with diabetes have a higher prevalence and risk of depression compared to the general population. However, the pathogenesis of diabetes-related depression remains unclear. As neuroinflammation is associated with diabetic complications and the pathophysiology of depression, this study aimed to elucidate the neuroimmunological mechanisms of diabetes-related depression. Methods: Male C57BL/6 mice were injected with streptozotocin (200 mg/kg, i.p.) to establish a diabetes model. After screening for hyperglycemia, diabetic mice were treated with the NLRP3 inhibitor MCC950 (20 mg/kg, i.p.) for 7 days. Then, the mice were assessed for metabolic indicators and depression-like behaviors, and their levels of central and peripheral inflammation were measured. To explore the mechanism of high glucose-induced microglial NLRP3 activation, we performed in vitro studies using BV2 mouse microglia. Furthermore, we focused on upstream signal I (TLR4/MyD88/NF-κB) and signal II (ROS/PKR/P 2 X 7 R/TXNIP) that may be involved in microglial inflammasome activation. Results: STZ-induced diabetic mice exhibited microglial NLRP3 inflammasome activation and developed depression-like behaviors. In vitro high-glucose (50 mM) environment promoted phosphorylation of the NF-κB p65 subunit through a TLR4/MyD88-independent way, thereby sensitizing the microglial NLRP3 inflammasome. Subsequently, high glucose activated the NLRP3 inflammasome via upregulating P 2 X 7 R, as well as enhancing intracellular ROS accumulation, promoting PKR phosphorylation and TXNIP expression, thereby facilitating IL-1β production and secretion. The NLRP3 inhibitor MCC950 significantly restored hyperglycemia-induced depression and activation of the microglial NLRP3 inflammasome, and reversed the elevation of IL-1β levels in hippocampus and serum. Conclusion: Microglial NLRP3 activation mediates the development of the depression-like behaviors evoked by STZ-induced diabetes in mice. Targeting the microglial NLRP3 inflammasome is a feasible strategy for the treatment of diabetes-related depression. This study provides new evidence for a comprehensive understanding of psychoneuroimmunology.