Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe and complex manifestation of SLE. The pathogenesis of diffuse NPSLE (dNPSLE)—which encompasses cognitive dysfunction, mood disorders, psychosis, and delirium—involves immune-mediated neuronal damage. However, the underlying mechanisms remain incompletely understood, particularly the role of microglial activation.

We used female MRL/lpr mice as a dNPSLE model, with MRL/mpj mice as controls. Transcriptomic analysis revealed significant upregulation of microglia-related pathways and IL-33 in MRL/lpr mice. IL-33 levels in patient serum and cerebrospinal fluid (CSF) were measured by ELISA. Brain expression of IL-33 in mice was evaluated by qRT-PCR, and its spatial relationship with microglia (IBA1⁺) was visualized via immunofluorescence. Microglial activation and phagocytosis were analyzed by flow cytometry. To inhibit IL-33 in vivo, the decoy receptor soluble ST2 (sST2) was infused intracerebroventricularly into MRL/lpr mice via mini-osmotic pumps. After 4 weeks, anxiety-like behavior and spatial memory were assessed using the open field test and Morris water maze (MWM). In BV2 microglial cells, we measured glycolytic enzyme (LDHA, PKM2, HK2) levels after IL-33 treatment using qRT-PCR and Western blot. Glycolysis was inhibited with 2-deoxy-D-glucose (2-DG), and microglial activation and phagocytosis were evaluated by qRT-PCR and flow cytometry.

IL-33 levels were elevated in the serum and CSF of dNPSLE patients and in the brains of MRL/lpr mice. Inhibition of IL-33 in vivo improved behavioral performance in the open field and MWM tests and reduced microglial phagocytosis. In vitro, IL-33 promoted anaerobic glycolysis in microglial cells, leading to enhanced activation and phagocytosis through upregulation of the glycolytic enzymes LDHA, PKM2, and HK2. Importantly, the pro-phagocytic and activating effects of IL-33 were abolished by glycolysis inhibition with 2-DG.

Our findings identify IL-33 as a key contributor to dNPSLE pathogenesis, driving microglial activation and phagocytosis via glycolytic reprogramming. These results highlight IL-33 as a potential therapeutic target for dNPSLE, warranting further investigation into its clinical translation.