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 language | English (US) |
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Article number | 111532 |
Journal | Cell Reports |
Volume | 41 |
Issue number | 4 |
DOIs | |
State | Published - Oct 25 2022 |
Keywords
- CP: Neuroscience
- NF-κB pathway
- NLRP3 inflammasome
- astrocyte
- caspase-1 pathway
- depression
- microglia
ASJC Scopus subject areas
- General Biochemistry, Genetics and Molecular Biology