Microglial NLRP3 inflammasome activates neurotoxic in-like mice

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 micro-glia-specific knockout of Nod-like receptor protein 3 (Nlrp3) markedly mitigates A1-like astrocyte induction, whereas astrocyte-specific symbolscript depletion is ineffective. Microglial symbolscript ablation also alleviates the neuronal dysfunction induced by A1-like astrocytes both symbolscript symbolscript and symbolscript symbolscript We further show that in microglia the NF-KB 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 neu-roinflammatory caspase-1 pathway in response to chronic stress and suggests a potential therapeutic strat-egy for depression.

Automated summary

This study reveals the involvement of neurotoxic reactive astrocytes and microglial NLRP3 inflammasome in depression. Knockout of Nlrp3 in microglial cells alleviates the induction of A1-like astrocytes and improves neuronal dysfunction. The NF-KB pathway and caspase-1 activation play crucial roles in the production of A1-like astrocytes.