Microglial NLRP3 inflammasome activates neurotoxic astrocytes in depression-like mice

Shanshan Li, Yinquan Fang, Yihe Zhang, Mengmeng Song, Xilin Zhang, Xiao Ding, Hang Yao, Miaomiao Chen, Yiming Sun, Jianhua Ding, Qin Wang, Ming Lu, Guangyu Wu, Gang Hu

Research output: Contribution to journalArticlepeer-review

Abstract

The function and regulation of different heterogeneous reactive states of astrocytes in depression remain unclear. Here, we demonstrate that neurotoxic reactive (A1-like) astrocytes are strongly induced, prior to behavioral impairments and dendritic atrophy, in depression-like mice. More interestingly, global or microglia-specific knockout of Nod-like receptor protein 3 (Nlrp3) markedly mitigates A1-like astrocyte induction, whereas astrocyte-specific Nlrp3 depletion is ineffective. Microglial Nlrp3 ablation also alleviates the neuronal dysfunction induced by A1-like astrocytes both in vitro and in vivo. We further show that in microglia the NF-κB pathway activates the NLRP3 inflammasome which in turn activates caspase-1 to induce the secretion of A1 inductors, leading to the production of A1-like astrocytes. Altogether, this study reveals the function of microglial NLRP3 inflammasome in the induction of neurotoxic astrocytes via activating neuroinflammatory caspase-1 pathway in response to chronic stress and suggests a potential therapeutic strategy for depression.

Original languageEnglish (US)
Article number111532
JournalCell Reports
Volume41
Issue number4
DOIs
StatePublished - Oct 25 2022
Externally publishedYes

Keywords

  • astrocyte
  • caspase-1 pathway
  • CP: Neuroscience
  • depression
  • microglia
  • NF-κB pathway
  • NLRP3 inflammasome

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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