Astrocytes reduce microglial activation and enhance adult hippocampal neurogenesis in acute inflammation

• Adult hippocampal neurogenesis is impaired in neuroinflammation. • Here, we examined the interaction between astrocytes and microglia in this process. • Astrocytes mitigate microglia inflammatory overactivation in culture conditions. • Astrocytic secretome (AS) alleviates behavioral symptoms of acute inflammation. • AS restores microglia homeostasis and cell proliferation in the neurogenic niche. Adult hippocampal neurogenesis is a major process of neuronal plasticity involved in mood regulation and memory and is tightly regulated by the neurogenic niche that relays signaling from the periphery. Neuroinflammation is principally mediated by microglia and strongly impairs adult neurogenesis, but the contribution of astrocytes to this effect is unclear. In this study, we used in vitro and in vivo approaches to investigate the role of astrocytes in the microglial inflammatory response and its impact on adult hippocampal neurogenesis. In vitro , we found that astrocytes attenuated the response of microglia to Lipopolysaccharide (LPS) inflammatory stimulation, through both secreted factors and direct membrane-bound interactions, with secreted factors displaying the strongest effect. Furthermore, astrocytes rescued the inhibition of adult hippocampal stem cell proliferation by LPS-stimulated microglia. In vivo , the administration of astrocyte-conditioned solution (ACS), containing the astrocyte secretome, attenuated LPS-induced sickness and depressive-like behavior, microglial and astrocytic reactivity in the dentate gyrus and restored the number of neural intermediate progenitors. Together, these findings indicate that astrocytes modulate microglia response to inflammatory cues and highlight the astrocytic secretome as a potent anti-inflammatory and pro-neurogenic agent, with potential implications for neuroinflammation-associated conditions such as Alzheimer’s disease and mood disorders.