Background Systemic lupus erythematosus (SLE) is an incurable autoimmune disease characterized by autoantibody deposition in tissues such as kidney, skin and lungs. Although less well understood, many patients with SLE experience neuropsychiatric symptoms that range from anxiety, depression and cognitive impairment to seizures and, in rare cases, psychosis. Collectively, these symptoms are referred to as central nervous system (CNS) lupus. In some cases, autoantibodies, such as anti-NMDAR or anti-phospholipid antibodies, promote CNS lupus. However, in many patients, CNS symptoms appear prior to serum autoantibody.
Methods Lupus strains of mice used in the project: 564Igi, NZB/W, and MRL/lpr. Behavior testing was performed at the Harvard Behavior core. RNA sequencing of microglia was performed at the MIT sequencing core.
Results We found that lupus-prone mice develop a distinct behavioral phenotype such as impaired learning and memory, anxiety and altered social behavior in which onset is age dependent. Examination of the brains of the lupus mice identified excess microglia engulfment of synapse material and a reduction in synapse density in the frontal cortex and hippocampus that correlates with the behavior phenotype. Comparison of RNA sequences of bulk sorted frontal cortex microglia identified differential expression of approximately 2000 genes between 564 and WT mice. To identify a role for interferon, RNA libraries were prepared from 564 and WT mice treated with a neutralizing antibody to IFNAR. Of the differentially expressed genes in lupus mice, about 20% were IFNa dependent. Notably, the microglia isolated from the lupus strain expressed an interferon gene signature that included IFNbeta but not IFNa. Pathway analysis of the interferon-dependent genes identified increased expression of genes important in phagocytosis and metabolic activity. Finally, reduction in peripheral levels of interferon alpha was protective from synapse loss and altered behavior (Bialas et al Nature 2017).
Conclusions We conclude that elevated blood levels of IFNa can promote neurological symptoms in mice. These findings suggest that therapies that block peripheral autoimmunity and reduce circulating levels of IFNa may protect against the symptoms of CNS lupus.
Acknowledgements Supported by grants from The Lupus Research Alliance (USA) and National Institutes of Health (USA).
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.