Microglial IL-27 modulates depressive symptoms induced by postnatal immune activation

Early-life inflammation increases the risk for mental disorders in later life by altering the long-term neuronal spine engulfment capacity of microglia. This process involves a bidirectional, tightly regulated interaction between the nervous and immune systems. However, the mechanisms whereby local immune responses modulate microglial cells are not fully understood. Here we define a critical role of microglial IL-27–IL-27Rα signaling in improving depressive symptoms induced by postnatal immune activation (PIA). IL-27 suppresses excessive microglial phagocytic activity, preserving synaptic density and preventing synaptic loss. Mechanistically, IL-27 activates STAT1 phosphorylation and nuclear translocation, inducing Trem2 expression—a key regulator of microglial phagocytosis—thus restoring synaptic stability. Genetic or pharmacological inhibition of Trem2 abolishes the antidepressant effects of IL-27, confirming the functional importance of this axis. These findings uncover a previously unrecognized IL-27–STAT1–Trem2 signaling axis regulating microglial function and synaptic integrity. Notably, IL-27 treatment also ameliorates behavioral deficits in a prenatal stress (PNS) model, underscoring its broader relevance across early-life adversity paradigms. Toxicological and immunological assessments demonstrate that IL-27 administration is well tolerated, with no significant adverse effects, supporting its translational viability. Together, these results position IL-27 as a promising immunotherapeutic candidate and drug target for mood disorders associated with neurodevelopmental immune dysregulation.