IL-33/ST2 deficiency induces depression-like behaviors through neuroinflammation in the medial prefrontal cortex and hippocampus

Depression remains a leading cause of global disability, yet its precise neurobiological underpinnings are incompletely understood. While inflammatory cytokines have been implicated in depressive pathology, the specific role of Interleukin-33 (IL-33) and its receptor ST2 in modulating microglial-mediated neuroinflammation has remained elusive. In this study, we reveal that deficiency of the IL-33/ST2 signaling axis in naive adult male mice selectively induces depression-like behaviors without impairing memory, motor coordination, or balance. This behavioral phenotype is mechanistically linked to heightened microglial activation, increased branching complexity, and exacerbated neuronal loss within the medial prefrontal cortex (mPFC) and dentate gyrus (DG). Furthermore, we demonstrate that IL-33 counteract LPS-induced microglial activation, nuclear translocation, and subsequent neuroinflammatory responses in vitro. Collectively, these findings delineate a novel neuroimmune pathway wherein IL-33/ST2 deficiency precipitates microglia-driven neuroinflammation, thereby contributing to depressive phenotypes.