Background/Purpose: About 20-40% of lupus patients suffer from diffuse neuropsychiatric manifestations of SLE, including cognitive impairment and depression. Although the pathogenesis is not well understood, brain barrier disruption and pro-inflammatory signaling within the brain parenchyma are thought to play an important role in disease development. Fingolimod, approved for the treatment of multiple sclerosis, functionally antagonizes sphingosine-1-phosphate (S1P) receptors and reduces the circulation of auto-reactive lymphocytes. In the CNS, fingolimod exerts a neuro-protective role, reducing pro-inflammatory cytokines and promoting brain barrier integrity. We have previously shown that fingolimod treatment reduces leukocyte infiltration of the choroid plexus in MRL/lpr mice and significantly attenuates cognitive dysfunction and depressive-like behavior. Here, we aimed to determine the effects of fingolimod on glial cells and pro-inflammatory cytokine signaling.

Methods: Ten-week-old female MRL/lpr mice were treated three times weekly with fingolimod (3 mg/kg) or vehicle alone (n=10/group) by intraperitoneal injection. After 10 weeks of treatment, brain cell suspensions generated from one hemisphere were analyzed by flow cytometry, and CD11b-positive CD64-positive CD45-low microglia, GFAP-positive astrocytes, and CD31-positive endothelial cells were sorted for RNA sequencing. Cortex and hippocampus samples were dissected from the other hemisphere of each brain and snap frozen for analysis of gene and protein expression.

Results: Flow cytometry revealed significant reductions in infiltrating leukocyte populations, including T cells, B cells, macrophages, neutrophils, eosinophils, and NK cells in fingolimod-treated mice. There was also a significant decrease in the number and/or activation of parenchymal cells, including microglia and astrocytes. Surprisingly, quantification of cytokine levels from cortical samples revealed a significant increase in IL-1a, IFNg, IFNb, and IL-12p70 in fingolimod-treated mice when compared with control mice. Similarly, increased expression of IL-1a, IL-1b, and MCP-1 was present in the hippocampi of treated mice. RNA sequencing results in the sorted cell populations are pending.

Conclusion: Fingolimod treatment reduces infiltration of leukocytes from the periphery into the CNS. Despite an unexpected increase in the expression of several brain cytokines with fingolimod treatment, the neurobehavioral deficits manifested by the MRL/lpr lupus strain were significantly attenuated. Our results highlight the complex role of the S1P signaling axis in the pathogenesis of neuropsychiatric SLE.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/neuropsychiatric-systemic-lupus-erythematosus-is-attenuated-by-sphingosine-1-phosphate-receptor-modulation/