Elsevier

Redox Biology

Volume 9, October 2016, Pages 178-187
Redox Biology

Research paper
Uncoupling protein 2 modulation of the NLRP3 inflammasome in astrocytes and its implications in depression

https://doi.org/10.1016/j.redox.2016.08.006Get rights and content
Under a Creative Commons license
open access

Highlights

  • UCP2 knockout exacerbates depressive behaviors in mice.

  • UCP2 knockout aggravates CMS-induced the inhibition of neurogenesis.

  • UCP2 deletion enhances NLRP3 inflammasome activation in hippocampus and in astrocyte.

  • UCP2 inhibits the ROS-TXNIP-NLRP3 signaling.

Abstract

Mitochondrial uncoupling protein 2 (UCP2) has been well characterized to control the production of reactive oxygen species (ROS) and astrocytes are the major cells responsible for the ROS production and the inflammatory responses in the brain. However, the function of UCP2 in astrocytes and the contribution of astrocytic UCP2 to depression remain undefined. Herein, we demonstrated that UCP2 knockout (KO) mice displayed aggravated depressive-like behaviors, impaired neurogenesis, and enhanced loss of astrocytes in the chronic mild stress (CMS)-induced anhedonia model of depression. We further found that UCP2 ablation significantly enhanced the activation of the nod-like receptor protein 3 (NLRP3) inflammasome in the hippocampus and in astrocytes. Furthermore, UCP2 deficiency promoted the injury of mitochondria, the generation of ROS and the physical association between thioredoxin-interacting protein (TXNIP) and NLRP3 in astrocytes. Moreover, transiently expressing exogenous UCP2 partially rescued the deleterious effects of UCP2 ablation on the astrocytes. These data indicate that UCP2 negatively regulates the activation of NLRP3 inflammasome and inhibited the ROS-TXNIP-NLRP3 pathway in astrocytes. Collectively, our findings reveal that UCP2 regulates inflammation responses in astrocytes and plays an important role in the pathogenesis of depression and that UCP2 may be a promising therapeutic target for depression.

Keywords

Uncoupling protein 2
NLRP3 inflammasome
Astrocyte
Depression
Reactive oxygen species

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These authors contribute equally to this work.