IKBKE contributes to neuropsychiatric manifestations in lupus-prone mice

ABSTRACT: Objectives. Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by multi-organ dysfunction. Neuropsychiatric SLE (NPSLE) occurs in 30~40% of patients with lupus and is the most severe presentation of SLE, frequently resulting in limitation of daily life. Recent studies have shown that microglia, tissue-resident macrophages in the central nervous system, are involved in the pathogenesis of NPSLE. Herein, we explored new therapeutic targets for NPSLE focusing on microglia. Methods. RNA sequencing of microglia in MRL/lpr, lupus-prone mice, as well as that of microglia cultured in vitro with cytokines were performed. A candidate gene, which could be a therapeutic target for NPSLE, was identified and its role on microglial activation and phagocytosis was investigated using specific inhibitors and siRNA. The effect of intracerebroventricular administration of the inhibitor on the behavioural abnormalities of MRL/lpr was also evaluated. Results. Transcriptome analysis revealed the upregulation of Ikbke, which encodes the inhibitor of nuclear factor kappa-B kinase epsilon (IKBKE) in both microglia from MRL/lpr mice and cytokine-stimulated microglia in vitro. Intracerebroventricular administration of an IKBKE inhibitor ameliorated cognitive function and suppressed microglial activation in MRL/lpr mice. Mechanistically, IKBKE inhibition reduced glycolysis, which dampened microglial activation and phagocytosis. Conclusions. These findings suggest that IKBKE plays a vital role in the pathogenesis of NPSLE via microglial activation, and it could serve as a therapeutic target for NPSLE.

ORGANISM(S): Mus musculus

PROVIDER: GSE199662 | GEO | 2022/09/13

REPOSITORIES: GEO