C57BL/6 Mouse Transgenic for Human MeCP2 as a Murine Model of Neuropsychiatric Lupus

Abstract

Abstract Introduction Systemic Lupus Erythematosus (SLE) impacts the central nervous system (CNS), leading to severe neurological and psychiatric manifestations known as neuropsychiatric lupus (NPSLE). To dissect the underlying disease mechanism and to discover novel drug targets of NPSLE, a robust animal model of NPSLE is highly desirable. Methods C57BL/6 mice transgenic for human MeCP2 (B6.MECP2Tg1) were phenotyped, including autoantibody profiling, analysis of cellularity and activation of splenic immune cells, proteinuria, as well as neuropsychiatric functions. Results The protein expression and phosphorylation of MeCP2 were significantly elevated in the brain of a spontaneous lupus mouse model MRL/lpr, compared to normal B6 mice. The B6.MECP2Tg1 transgenic mice exhibited elevated proteinuria, increased proinflammatory cytokines, altered autoantibody profiles, augmented IgG deposition and macrophage infiltration in the kidney, compared to B6 mice. Effector memory T cells, germinal center B cells and plasma B cells were markedly increased in the female B6.MeCP2Tg1 mice. In addition, B6.MECP2Tg1 mice exhibited anxiety and depression-like behavior, as well as cognitive disorders as early as 9 weeks of age. The abnormal behaviors of the B6.MECP2Tg1 mice are associated with the aberrant neurogenesis and inflammation in the hippocampus, immune cell infiltration in the choroid plexus, as well as the disrupted blood-brain barrier (BBB) and activated microglia, as demonstrated by immunofluorescence microscopy. Conclusion Collectively, this work demonstrates that B6.MECP2Tg1 mice exhibit lupus-like phenotypes as well as robust CNS dysfunctions, suggesting it may represent a new animal model for NPSLE.