FTY720 attenuates behavioral deficits in a murine model of systemic lupus erythematosus

Shi, Dongyan; Tian, Tongguan; Shu, Yao; Cao, Kelei; Zhu, Xingxing; Zhang, Mingshun; Wen, Shuang; Li, Longjun; Shi, Meiqing; Zhou, Hong

doi:10.1016/j.bbi.2018.03.009

Cited by 34 publications

(17 citation statements)

References 50 publications

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“…C5a receptor blockade ameliorates blood–brain barrier disruption and attenuates behavioral abnormalities in MRL/ lpr mice , revealing a potential therapeutic target for CD. While sphingosine 1‐phosphate receptor modulation with FTY720 stabilizes the blood–brain barrier in MRL/ lpr mice and mitigates CD , its use in SLE will be limited by its known toxicity.…”

Section: Introductionmentioning

confidence: 99%

Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

Kello

Anderson

Diamond

2019

Arthritis & Rheumatology

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Cognitive dysfunction (CD) is an insidious and underdiagnosed manifestation of systemic lupus erythematosus (SLE) that has a considerable impact on quality of life, which can be devastating. Given the inconsistencies in the modes of assessment and the difficulties in attribution to SLE, the reported prevalence of CD ranges from 5% to 80%. Although clinical studies of SLE‐related CD have been hampered by heterogeneous subject populations and a lack of sensitive and standardized cognitive tests or other validated objective biomarkers for CD, there are, nonetheless, strong data from mouse models and from the clinical arena that show CD is related to known disease mechanisms. Several cytokines, inflammatory molecules, and antibodies have been associated with CD. Proposed mechanisms for antibody‐ and cytokine‐mediated neuronal injury include the abrogation of blood–brain barrier integrity with direct access of soluble molecules in the circulation to the brain and ensuing neurotoxicity and microglial activation. No treatments for SLE‐mediated CD exist, but potential candidates include agents that inhibit microglial activation, such as angiotensin‐converting enzyme inhibitors, or that protect blood–brain barrier integrity, such as C5a receptor blockers. Structural and functional neuroimaging data have shown a range of regional abnormalities in metabolism and white matter microstructural integrity in SLE patients that correlate with CD and could in the future become diagnostic tools and outcome measures in clinical trials aimed at preserving cognitive function in SLE.

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Section: Introductionmentioning

confidence: 99%

Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

Kello

Anderson

Diamond

2019

Arthritis & Rheumatology

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“…Recently, fingolimod was shown to ameliorate behavioral deficits in B6.MRL/lpr mice ( 80 ), a model which had not previously been shown to exhibit a robust neuropsychiatric phenotype. In this cohort of only 4–6 mice per group and after 12 weeks of treatment, Shi et al used the tail suspension test to measure depression-like behavior.…”

Section: Discussionmentioning

confidence: 99%

Neuropsychiatric Systemic Lupus Erythematosus Is Dependent on Sphingosine-1-Phosphate Signaling

et al. 2018

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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.

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“…The mice in group C received 2 mg/kg FTY720 each day by oral from the day of immunization until the mice were sacrificed. 10 , 11 In the model group of CIA model and the control group, mice accepted saline instead.…”

Section: Methodsmentioning

confidence: 99%

FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4+ T Lymphocytes

Zhu

Wen

et al. 2021

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Background: Fingolimod (FTY720), a novel immunomodulator, was found to suppress the severity of collagen-induced arthritis (CIA) in mice. However, the potential molecular mechanisms are still unknown, and the effect of FTY720 on the recruitment of immune cells in the affected joints in the CIA model is not clear. Materials and Methods: Following the oral administration of FTY720 (2 mg/kg) was treated into CIA mice per day for 35 days, intravital microscopy and immunofluorescence assays were performed to examine immune cell recruitment in the affected joints. Human MH7A synoviocytes were stimulated with tumour necrosis factor (TNF)-α and incubated with FTY720. Interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-8 (IL-8) mRNA and protein expression were evaluated using RT-PCR and enzyme-linked immunosorbent assay, respectively. Signal transduction pathway protein expression was measured by Western blotting. Nuclear translocation of nuclear factor (NF)-κB was also analyzed by fluorescence microscopy. Results: In vivo experiments showed that FTY720 inhibited the recruitment of CD4 + lymphocytes in the affected joints of CIA mice. FTY720 reduced the secretion of IL-1β, IL-6, and IL-8 from TNF-α-stimulated MH7A cells in a dose-dependent manner. FTY720 also inhibited TNF-α-induced phosphorylation of NF-κBp65 and IκBα, as well as NF-κBp65 nuclear translocation, in a dose-and time-dependent manner. Interestingly, FTY720 blocked PI3K/Akt, the upstream targets of the NF-κB pathway. Conclusion: Our findings demonstrated that oral administration of FTY720 exerted beneficial effects in CIA mice by inhibiting CD4 + T lymphocyte recruitment to the affected joints. Our data also indicated that FTY720 inhibited TNF-α-induced inflammation by suppressing the AKT/PI3K/NF-κB pathway in MH7A cells.

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FTY720 attenuates behavioral deficits in a murine model of systemic lupus erythematosus

Cited by 34 publications

References 50 publications

Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

Neuropsychiatric Systemic Lupus Erythematosus Is Dependent on Sphingosine-1-Phosphate Signaling

FTY720 Inhibits the Development of Collagen-Induced Arthritis in Mice by Suppressing the Recruitment of CD4+ T Lymphocytes

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