Neuropsychiatric Lupus: Pathogenic Mechanisms and Novel Therapeutic Strategies
Mike, Elise V.
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Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that predominantly affects women of color. About 20 to 40% of lupus patients suffer from diffuse neuropsychiatric manifestations of SLE (NPSLE), including cognitive impairment and depression. The pathogenesis of NPSLE is not well understood, and current treatment strategies are suboptimal and generally noncurative. Brain barrier disruption, which allows peripheral mediators to enter the central nervous system (CNS), and proinflammatory signaling within the brain parenchyma are both thought to play an important role in disease development. Modulation of neuroinflammation is a potential therapeutic strategy. Here, we investigated the effects of altering the brain microenvironment through genetic and pharmacological means. Lipocalin-2, an acute phase reactant protein upregulated systemically in SLE, promotes neuroinflammation through inducing brain barrier disruption, glial activation, and neurotoxicity. We hypothesized that the absence of LCN2 would ameliorate NPSLE. To test this hypothesis, lupus-prone B6.Slel.S1e3 (Sle1,3) mice, Sle1,3-LCN2 knockout (KO), B6.LCN2KO, and B6 mice were evaluated. Sle1,3 mice exhibited significant impairment in spatial and recognition memory and depression-like behavior when compared with B6 mice, and these deficits were significantly attenuated in Sle1,3LCN2KO mice. Flow cytometry of hemisected brain lysates showed a significant increase in brain infiltrating cells, including CD4+ and CD8+ T cells, that was not reduced with LCN2 deficiency. Immunofluorescence staining of the hippocampus revealed a preponderance of apoptotic microglia and neurons in Sle1,3 mice that was reduced with LCN2 deficiency. Transcriptome profiling of sorted microglia showed that several genes, upregulated in Sle1,3 mice and involved in inflammation and memory, were normalized in Sle1,3-LCN2KO mice. Additionally, in two independent large cohorts, NPSLE patients displayed high CSF levels of LCN2. These demonstrate that LCN2 deficiency attenuates neurobehavioral deficits, reduces apoptosis in the brain, and modulates microglia morphology. Moreover, our results show that LCN2 regulates microglial expression of genes essential to NPSLE development. LCN2 secretion can be stimulated by sphingosine-1-phosphate (S1P), a bioactive sphingolipid involved in several immune processes. Fingolimod, approved for the treatment of multiple sclerosis, functionally antagonizes S1P receptors and reduces the circulation of autoreactive lymphocytes. In the CNS, fingolimod exerts a neuroprotective role, reducing pro-inflammatory cytokines and promoting brain barrier integrity. We investigated the effects of fingolimod in MRL-1pr/lpr mice, a classic spontaneous NPSLE model, and we hypothesized that fingolimod treatment would attenuate disease. Fingolimod-treated mice exhibited significantly improved visual and recognition memory and displayed a reduction in depression-like behavior, demonstrating an amelioration of the NPSLE phenotype. A significant reduction of CD4+ and CD8+ T cell infiltration of the choroid plexus in the lateral ventricles was also observed by immunofluorescence staining and flow cytometry. There was also a significant decrease in the number and/or activation of parenchymal cells, including microglia and astrocytes. These results highlight the important role of SIP in the pathogenesis of neurocognitive manifestations of SLE. Taken together, our results highlight the LCN2 pathway and the SIP signaling axis as novel therapeutic targets and elucidate two potential determinants of disease development.