Microglial NLRP3 inflammasome activates neurotoxic astrocytes in depression-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 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. [Display omitted] •Neurotoxic A1-like astrocytes are enhanced in the CMS depression mouse model•NLRP3 inflammasome in microglia but not in astrocytes induces A1-like astrocytes•NLRP3 inflammasome activates microglia and promotes A1 cocktail secretion•NF-κB and caspase-1 pathways are involved in NLRP3-induced astrocyte reactivity Li et al. report that microglial NLRP3 inflammasome induces neurotoxic A1-like astrocytes and neuronal dysfunction in response to chronic mild stress in mice through pro-A1 astrocyte cytokines, involving upstream NF-κB pathway and downstream caspase-1 pathway. Their results suggest crucial roles of microglial NLRP3 in neurotoxic astrocyte reactivity in major depression.