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

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

  • Prog Neuropsychopharmacol Biol Psychiatry. 2023 May 18;110796. doi: 10.1016/j.pnpbp.2023.110796.
Wen-Jun Su 1,  Jia-Mei Li 2,  Ting Zhang 3,  Zhi-Yong Cao 4,  Ting Hu 3,  Shi-Yang Zhong 3,  Zhang-Yang Xu 5,  Hong Gong 6,  Chun-Lei Jiang 7
Affiliations

Affiliations

  • 1 Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai 200433, China. Electronic address: suwenjun1992@163.com.
  • 2 Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai 200433, China; The 971st Hospital of PLA Navy, Qingdao 266072, China.
  • 3 Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai 200433, China.
  • 4 Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai 200433, China; Department of Psychiatry and Sleep Disorder, The 904th Hospital of PLA, Changzhou 213004, China.
  • 5 Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai 200433, China; The Battalion 3 of Cadet Brigade, School of Basic Medicine, Naval Medical University, Shanghai 200433, China.
  • 6 Department of Developmental Neuropsychology, Faculty of Medical Psychology, Army Medical University (Third Military Medical University), Chongqing 400038, China.
  • 7 Department of Stress Medicine, Faculty of Psychology, Naval Medical University, Shanghai 200433, China. Electronic address: cljiang@vip.163.com.
PMID: 37209992 DOI: 10.1016/j.pnpbp.2023.110796
Abstract

Background: 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.

Methods: 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).

Results: 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.

Conclusion: 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.

Keywords

Depression; Diabetes; Microglia; Neuroinflammation; nlrp3 inflammasome.

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