The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

Gulinello, Maria; Putterman, Chaim

doi:10.1155/2011/207504

Cited by 115 publications

(92 citation statements)

References 252 publications

(274 reference statements)

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“…In a special breed of lupus-prone mice, the MRL/MPJ-Fas lpr (thereafter named MRL-lpr) substrain, the onset of systemic autoimmunity and inflammation is accompanied by various deficits in brain function comparable to that observed in SLE patients, providing a useful model to study NPSLE. Interestingly, NP manifestations can also appear early in these mice and are primarily driven by autoimmune process [16]. This review will focus on the validity of the MRL model in relation with cognition, and a particular emphasis is given to consideration of these mice as a model of choice to evaluate potential neuroprotective drugs.…”

Section: Introductionmentioning

confidence: 99%

Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: The MRL-lpr mouse strain as a model

Jeltsch-David

Muller

2014

Autoimmunity Reviews

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Mouse models of autoimmunity, such as (NZB×NZW)F1, MRL/MpJ-Fas(lpr) (MRL-lpr) and BXSB mice, spontaneously develop systemic lupus erythematosus (SLE)-like syndromes with heterogeneity and complexity that characterize human SLE. Despite their inherent limitations, such models have highly contributed to our current understanding of the pathogenesis of SLE as they provide powerful tools to approach the human disease at the genetic, cellular, molecular and environmental levels. They also allow novel treatment strategies to be evaluated in a complex integrated system, a favorable context knowing that very few murine models that adequately mimic human autoimmune diseases exist. As we move forward with more efficient medications to treat lupus patients, certain forms of the disease that requires to be better understood at the mechanistic level emerge. This is the case of neuropsychiatric (NP) events that affect 50-60% at SLE onset or within the first year after SLE diagnosis. Intense research performed at deciphering NP features in lupus mouse models has been undertaken. It is central to develop the first lead molecules aimed at specifically treating NPSLE. Here we discuss how mouse models, and most particularly MRL-lpr female mice, can be used for studying the pathogenesis of NPSLE in an animal setting, what are the NP symptoms that develop, and how they compare with human SLE, and, with a critical view, what are the neurobehavioral tests that are pertinent for evaluating the degree of altered functions and the progresses resulting from potentially active therapeutics.

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Section: Introductionmentioning

confidence: 99%

Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: The MRL-lpr mouse strain as a model

Jeltsch-David

Muller

2014

Autoimmunity Reviews

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“…[7][8][9][10] MRL/lpr mice differ from the congenic MRL/ MpJ (MRL +/+ ) strain by the absence of the pro-apoptotic membrane Fas protein, due to a retroviral insertion in the Tnfrsf6 gene. [11][12][13] Using these mice, our studies also show that the loss of BBB integrity is complement dependent.…”

Section: M M U N O L O G Y O R I G I N a L A R T I C L Ementioning

confidence: 99%

C5a induces caspase‐dependent apoptosis in brain vascular endothelial cells in experimental lupus

et al. 2016

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SummaryBlood-brain barrier (BBB) dysfunction complicates central nervous system lupus, an important aspect of systemic lupus erythematosus. To gain insight into the underlying mechanism, vascular corrosion casts of brain were generated from the lupus mouse model, MRL/lpr mice and the MRL/MpJ congenic controls. Scanning electron microscopy of the casts showed loss of vascular endothelial cells in lupus mice compared with controls. Immunostaining revealed a significant increase in caspase 3 expression in the brain vascular endothelial cells, which suggests that apoptosis could be an important mechanism causing cell loss, and thereby loss of BBB integrity. Complement activation occurs in lupus resulting in increased generation of circulating C5a, which caused the endothelial layer to become 'leaky'. In this study, we show that C5a and lupus serum induced apoptosis in cultured human brain microvascular endothelial cells (HBMVECs), whereas selective C5a receptor 1 (C5aR1) antagonist reduced apoptosis in these cells, demonstrating C5a/C5aR1-dependence. Gene expression of initiator caspases, caspase 1 and caspase 8, and proapoptotic proteins death-associated protein kinase 1, Fas-associated protein (FADD), cell death-inducing DNA fragmentation factor 45 000 MW subunit A-like effector B (CIDEB) and BCL2-associated X protein were increased in HBMVECs treated with lupus serum or C5a, indicating that both the intrinsic and extrinsic apoptotic pathways could be critical mediators of brain endothelial cell apoptosis in this setting. Overall, our findings suggest that C5a/C5aR1 signalling induces apoptosis through activation of FADD, caspase 8/3 and CIDEB in brain endothelial cells in lupus. Further elucidation of the underlying apoptotic mechanisms mediating the reduced endothelial cell number is important in establishing the potential therapeutic effectiveness of C5aR1 inhibition that could prevent and/or reduce BBB alterations and preserve the physiological function of BBB in central nervous system lupus.

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“…Although diverse behavioral batteries can be designed 4,5 , listed below are the procedures that have been used to successfully establish an animal model of neuropsychiatric lupus 6 . This battery is repeatedly applied in both sub-chronic and chronic models of disease (Figure 1), such as mild cognitive impairment and Alzheimer's disease Continuous video-recording and analysis of behavior in a home-cage-like environment were first reported in 2007 11 .…”

Section: Refinements In Behavioral Phenotyping Of Diseased Micementioning

confidence: 99%

Behavioral Phenotyping of Murine Disease Models with the Integrated Behavioral Station (INBEST)

Šakić

Cooper

Taylor

et al. 2015

JoVE

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Due to rapid advances in genetic engineering, small rodents have become the preferred subjects in many disciplines of biomedical research. In studies of chronic CNS disorders, there is an increasing demand for murine models with high validity at the behavioral level. However, multiple pathogenic mechanisms and complex functional deficits often impose challenges to reliably measure and interpret behavior of chronically sick mice. Therefore, the assessment of peripheral pathology and a behavioral profile at several time points using a battery of tests are required. Video-tracking, behavioral spectroscopy, and remote acquisition of physiological measures are emerging technologies that allow for comprehensive, accurate, and unbiased behavioral analysis in a home-base-like setting. This report describes a refined phenotyping protocol, which includes a custom-made monitoring apparatus (Integrated Behavioral Station, INBEST) that focuses on prolonged measurements of basic functional outputs, such as spontaneous activity, food/water intake and motivated behavior in a relatively stress-free environment. Technical and conceptual improvements in INBEST design may further promote reproducibility and standardization of behavioral studies.

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The MRL/lpr Mouse Strain as a Model for Neuropsychiatric Systemic Lupus Erythematosus

Cited by 115 publications

References 252 publications

Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: The MRL-lpr mouse strain as a model

Neuropsychiatric systemic lupus erythematosus and cognitive dysfunction: The MRL-lpr mouse strain as a model

C5a induces caspase‐dependent apoptosis in brain vascular endothelial cells in experimental lupus

Behavioral Phenotyping of Murine Disease Models with the Integrated Behavioral Station (INBEST)

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