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

• Published in: Progress in neuro-psychopharmacology & biological psychiatry 2023-08, Vol.126, p.110796-110796, Article 110796
• Main Authors: Su, Wen-Jun, Li, Jia-Mei, Zhang, Ting, Cao, Zhi-Yong, Hu, Ting, Zhong, Shi-Yang, Xu, Zhang-Yang, Gong, Hong, Jiang, Chun-Lei
• Format: Article
• Language: English
• Subjects: Depression; Diabetes; Microglia; Neuroinflammation; Nlrp3 inflammasome
• ISSN: 0278-5846; 1878-4216
• DOI: 10.1016/j.pnpbp.2023.110796

Abundant evidence suggests that the prevalence and risk of depression in people with diabetes is high. However, the pathogenesis of diabetes-related depression remains unclear. Since neuroinflammation is associated with the pathophysiology of diabetic complications and depression, this study aims to elucidate the neuroimmune mechanism of diabetes-related depression. Male C57BL/6 mice were injected with streptozotocin to establish a diabetes model. After screening, diabetic mice were treated with the NLRP3 inhibitor MCC950. Then, metabolic indicators and depression-like behaviors were evaluated in these mice, as well as their central and peripheral inflammation. To explore the mechanism of high glucose-induced microglial NLRP3 inflammasome activation, we performed in vitro studies focusing on its canonical upstream signal I (TLR4/MyD88/NF-κB) and signal II (ROS/PKR/P2X7R/TXNIP). Diabetic mice exhibited depression-like behaviors and activation of NLRP3 inflammasome in hippocampus. In vitro high-glucose (50 mM) environment primed microglial NLRP3 inflammasome by promoting NF-κB phosphorylation in a TLR4/MyD88-independent manner. Subsequently, high glucose activated the NLRP3 inflammasome via enhancing intracellular ROS accumulation, upregulating P2X7R, as well as promoting PKR phosphorylation and TXNIP expression, thereby facilitating the production and secretion of IL-1β. Inhibition of NLRP3 with MCC950 significantly restored hyperglycemia-induced depression-like behavior and reversed the increase in IL-1β levels in the hippocampus and serum. The activation of NLRP3 inflammasome, probably mainly in hippocampal microglia, mediates the development of depression-like behaviors in STZ-induced diabetic mice. Targeting the microglial inflammasome is a feasible strategy for the treatment of diabetes-related depression. Schematic diagram of the role and molecular mechanisms of microglial NLRP3 inflammasome activation in mediating diabetes-related depression. IL-1β: interleukin-1 beta; NLRP3: NOD-, leucine-rich repeat (LRR)-, and pyrin domain (PYD)-containing protein 3; ASC: apoptosis-associated speck-like protein containing a caspase recruitment domain; TLR4: Toll-like receptor 4; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; ROS: reactive oxygen species; TXNIP: thioredoxin-interacting protein; PKR: double-stranded RNA-dependent protein kinase; P2X7R: purinergic receptor P2X, ligand-gated ion channel 7; ATP: adenosine triphosphate. [Display