The potential pathogenetic link between peripheral immune activation and the central innate immune response in neuropsychiatric systemic lupus erythematosus

Tomita, Michiyo; Khan, Raza L; Blehm, Benjamin H; Santoro, Thomas J.

doi:10.1016/j.mehy.2003.10.009

Cited by 29 publications

(16 citation statements)

References 94 publications

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“…Indeed, the Fn14 staining of brain endothelial cells in MRL/lpr mice demonstrated above would also point towards a possible BBB effect. By increasing the permeability of the BBB, as we demonstrated in MRL/lpr Fn14WT mice, TWEAK may promote the diffusion of pathogenic moieties from the circulation into the brain, including autoantibodies, activated lymphocytes and cytokines [48]. Thus, enhanced protection of the brain from the harmful effects of autoantibodies and cytokines coming from the circulation is likely to have contributed to preserved neuronal function and the improved neurobehavioral profile that we found in MRL/lpr Fn14KO mice.…”

Section: Discussionmentioning

confidence: 72%

Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway

Wen

Xia

Stock

et al. 2013

Journal of Autoimmunity

104

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Given the early onset of neuropsychiatric disease and the potential response to immunosuppressive therapy, neuropsychiatric disease is considered a primary disease manifestation in SLE. However, the pathogenesis is not fully understood and optimal treatment has yet to be determined. TWEAK is a TNF family ligand that mediates pleotropic effects through its receptor Fn14, including the stimulation of inflammatory cytokines by astrocytes, endothelial cells, and other non-hematopeotic cell types, and induction of neuronal death. Furthermore, TWEAK-inducible mediators are implicated in neuropsychiatric lupus. Thus, we hypothesized that the TWEAK/Fn14 pathway may be involved in the pathogenesis of neuropsychiatric SLE. We generated MRL-lpr/lpr (MRL/lpr) mice deficient for Fn14, the sole known signaling receptor for TWEAK. Neuropsychiatric disease was compared in age- and gender-matched MRL/lpr Fn14 wild type (WT) and knockout (KO) mice, using a comprehensive battery of neurobehavioral tests. We found that MRL/lpr Fn14WT mice displayed profound depression-like behavior as seen by increased immobility in a forced swim test and loss of preference for sweetened fluids, which were significantly ameliorated in Fn14KO mice. Similarly, MRL/lpr Fn14WT mice had impaired cognition, and this was significantly improved in Fn14KO mice. To determine the mechanism by which Fn14 deficiency ameliorates neuropsychiatric disease, we assessed the serum levels of autoantibodies and local expression of cytokines in the cortex and hippocampus of lupus mice. No significant differences were found in the serum levels of antibodies to nuclear antigens, or autoantibodies specifically associated with neuropsychiatric disease, between MRL/lpr Fn14WT and KO mice. However, MRL/lpr Fn14KO mice had significantly decreased brain expression of RANTES, C3, and other proinflammatory mediators. Furthermore, MRL/lpr Fn14KO mice displayed improved blood brain barrier integrity. In conclusion, several central manifestations of neuropsychiatric lupus, including depression-like behavior and altered cognition, are normalized in MRL/lpr mice lacking Fn14. Our results are the first to indicate a role for the TWEAK/Fn14 pathway in the pathogenesis of neuropsychiatric lupus, and suggest this ligand-receptor pair as a potential therapeutic target for a common and dangerous disease manifestation.

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Section: Discussionmentioning

confidence: 72%

Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway

Wen

Xia

Stock

et al. 2013

Journal of Autoimmunity

104

View full text Add to dashboard Cite

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“…The results indicate that the proinflammatory cytokine genes for interferon (IFN)-γ, IL-1, IL-6 and IL-10, which have been shown to induce cognitive and emotional impairments, are selectively up-regulated in the hippocampi of MRL-lpr mice. Thus, proinflammatory cytokines may play a role in the cognitive aberrations observed in MRL-lpr mice and, by extension, in lupus [145]. Finally, increased expression of TNF and of its receptor TNFR1, which are moreover implicated in induction of inflammation and degeneration/ apoptosis in the CNS, had been reported in the brain of MRL-lpr mice [146].…”

Section: Cytokinesmentioning

confidence: 96%

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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“…In addition to peripheral organ dysfunction in SLE, there is a high incidence of neuropsychiatric symptoms especially headaches, cognitive dysfunction, and psychiatric disorders [1], with roughly 40–70% of SLE patients demonstrating affective disorders [2]. Brain pathology, loss of integrity of the blood-brain barrier and autoantibodies are thought to play a role in neuropsychiatric systemic lupus erythematosus (NP-SLE), although some patients with behavioral symptoms have histologically normal brain tissue and no identifiable markers in serum or CSF [3–11]. …”

Section: Introductionmentioning

confidence: 99%

“…In addition, we discuss experimental data pointing to viable pathogenic mechanisms that underlie CNS involvement in SLE. Excellent reviews about other aspects of this and other murine models of lupus can be found elsewhere [3, 11, 21–34]. …”

Section: Introductionmentioning

confidence: 99%

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

Gulinello

Putterman

2011

Journal of Biomedicine and Biotechnology

115

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To date, CNS disease and neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. In this review, we focus on a specific mouse model of lupus and the ways in which this model reflects some of the most common manifestations and potential mechanisms of human NP-SLE. The mouse MRL lymphoproliferation strain (a.k.a. MRL/lpr) spontaneously develops the hallmark serological markers and peripheral pathologies typifying lupus in addition to displaying the cognitive and affective dysfunction characteristic of NP-SLE, which may be among the earliest symptoms of lupus. We suggest that although NP-SLE may share common mechanisms with peripheral organ pathology in lupus, especially in the latter stages of the disease, the immunologically privileged nature of the CNS indicates that early manifestations of particularly mood disorders maybe derived from some unique mechanisms. These include altered cytokine profiles that can activate astrocytes, microglia, and alter neuronal function before dysregulation of the blood-brain barrier and development of clinical autoantibody titres.

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The potential pathogenetic link between peripheral immune activation and the central innate immune response in neuropsychiatric systemic lupus erythematosus

Cited by 29 publications

References 94 publications

Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway

Neuropsychiatric disease in murine lupus is dependent on the TWEAK/Fn14 pathway

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

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

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