Abstract
About 40% of patients with systemic lupus erythematosus experience diffuse neuropsychiatric manifestations, including impaired cognition and depression. Although the pathogenesis of diffuse neuropsychiatric SLE (NPSLE) is not fully understood, loss of brain barrier integrity, autoreactive antibodies, and pro-inflammatory cytokines are major contributors to disease development. Fingolimod, a sphingosine-1-phosphate (S1P) receptor modulator, prevents lymphocyte egress from lymphoid organs through functional antagonism of S1P receptors. In addition to reducing the circulation of autoreactive lymphocytes, fingolimod has direct neuroprotective effects such as preserving brain barrier integrity and decreasing pro-inflammatory cytokine secretion by astrocytes and microglia. Given these effects, we hypothesized that fingolimod would attenuate neurobehavioral deficits in MRL-lpr/lpr (MRL/lpr) mice, a validated neuropsychiatric lupus model. Fingolimod treatment was initiated after the onset of disease, and mice were assessed for alterations in cognitive function and emotionality. We found that fingolimod significantly attenuated spatial memory deficits and depression-like behavior in MRL/lpr mice. Immunofluorescent staining demonstrated a dramatic lessening of brain T cell and macrophage infiltration, and a significant reduction in cortical leakage of serum albumin, in fingolimod treated mice. Astrocytes and endothelial cells from treated mice exhibited reduced expression of inflammatory genes, while microglia showed differential regulation of key immune pathways. Notably, cytokine levels within the cortex and hippocampus were not appreciably decreased with fingolimod despite the improved neurobehavioral profile. Furthermore, despite a reduction in splenomegaly, lymphadenopathy, and circulating autoantibody titers, IgG deposition within the brain was unaffected by treatment. These findings suggest that fingolimod mediates attenuation of NPSLE through a mechanism that is not dependent on reduction of autoantibodies or cytokines, and highlight modulation of the S1P signaling pathway as a novel therapeutic target in lupus involving the central nervous system.
Highlights
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoreactive B and T lymphocytes, the overproduction of autoreactive antibodies, and tissue deposition of immune complexes
There were no significant differences in total track length (control vs. treated: 3,037 ± 134 cm vs. 3,104 ± 140 cm, t(30) = 0.34, p = 0.73, Figure 1B), number of rears (control vs. treated: 36.5 ± 5.2 vs. 40.25 ± 6.1, t(30) = 0.45, p = 0.66, Figure 1C), and amount of time spent in the center between fingolimod and control treated mice
The time spent running, orienting, and remaining still were not different between the two groups. This suggests that the differences seen in the forced swim test (FST) after fingolimod treatment are not the result of alterations in locomotion, but rather are due to a reduction of the disturbed emotionality seen in MRL/lpr mice at this age
Summary
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoreactive B and T lymphocytes, the overproduction of autoreactive antibodies, and tissue deposition of immune complexes. 40% of SLE patients present with neurological or psychiatric symptoms that precede or may occur independently of active systemic disease and significantly decrease quality of life [4]. These neuropsychiatric lupus (NPSLE) manifestations include a wide array of clinical presentations that can be broadly categorized as focal or diffuse [5]. While focal symptoms such as seizure and stroke are known to be caused by underlying vasculopathy or thromboembolism, the pathophysiology of diffuse neuropsychiatric manifestations, including cognitive dysfunction, memory loss, and affective disorders, is not fully understood
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