Abstract

Early-life inflammation increases the risk of mental disorders later in life by altering the long-term microglial capacity for neuronal spine engulfment, highlighting a tightly regulated neuroimmune interaction. However, how local immune signals modulate microglial function remains unclear. Here, we show that microglia-associated IL-27-IL-27Rα signaling alleviates depression-like behaviors induced by postnatal immune activation (PIA). At the cellular level, IL-27 treatment suppresses excessive microglial phagocytic activity, thereby preserving synaptic density and preventing synaptic loss. Notably, its beneficial effects extend beyond the PIA model, as IL-27 also ameliorates behavioral deficits in prenatal stress-exposed mice. Importantly, animal safety evaluations support the tolerability of IL-27 administration. These effects are mediated, in part, through the STAT1-Trem2-dependent mechanism. Collectively, these findings support IL-27 as a protective immunoregulatory factor and highlight its therapeutic potential for mood disorders associated with neurodevelopmental immune dysregulation.