Tu123 - Contribution of Phosphodiesterase 1B to Neuropsychiatric Manifestations in Lupus-prone Mice via Microglial Activation

Abstract Text:

Background: Recent studies have shown that abnormal activation of microglia is involved in the pathogenesis of neuropsychiatric systemic lupus erythematosus (NPSLE). The aim of this study was to identify potential novel therapeutic targets for NPSLE.

Methods: RNA sequencing (RNA-Seq) of microglia isolated from lupus-prone MRL/lpr mice and control strain MRL/MpJ mice was performed to explore candidate genes involved in microglial activation. We generated microglia-specific conditional knockout (cKO) mice to evaluate the function of the candidate gene in microglia. Gene expression of proinflammatory cytokines by real-time PCR and phagocytosis assays were performed in microglia from cKO mice. RNA-Seq and pathway analysis of cKO and control mice microglia were conducted to clarify the mechanism of altered expression of the candidate gene. An imiquimod-induced lupus model was used as an NPSLE model in cKO and control mice. The effects of an inhibitor of the candidate protein were evaluated in MRL/lpr mice via intracerebroventricular administration. Neurological manifestations were assessed by behavioral tests.

Results: Among up-regulated genes in RNA-Seq, we focused on phosphodiesterase 1b (Pde1b), one of the top-fold changed genes. Gene expression of proinflammatory cytokines and phagocytosis were significantly suppressed in Pde1b cKO microglia. Gene Ontology analysis showed that the top five down-regulated pathways were related to the proinflammatory response. Hk1, a glycolytic enzyme, was involved in all these pathways. Pde1b cKO mice showed reduced imiquimod-induced behavioral abnormalities. Intracerebroventricular administration of the PDE1B inhibitor ameliorated behavioral alterations in MRL/lpr mice.

Conclusion: Our data suggest that Pde1b could be a novel therapeutic target for NPSLE.