Aberrant cytokine gene expression in the hippocampus in murine systemic lupus erythematosus

Tomita, Michiyo; Holman, Brita J.; Santoro, Thomas J.

doi:10.1016/s0304-3940(01)01679-2

Cited by 43 publications

(18 citation statements)

References 18 publications

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“…Pro-inflammatory cytokines are upregulated systemically (Tang et al, 1991;Tsai et al, 1995) and in the hippocampus of MRL-lpr mice (Tomita et al, 2001). Since they appear to alter central neurotransmission (Zalcman et al, 1994), one may hypothesize that an accumulation of serotonergic neurotoxins, such as 5,7-dihydroxytryptamine (Tabatabaie et al, 1993), could compromise the survival of hippocampal neurons.…”

Section: Discussionmentioning

confidence: 99%

Hippocampal damage in mouse and human forms of systemic autoimmune disease

Ballok¹,

Woulfe

Sur

et al. 2004

Hippocampus

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Systemic lupus erythematosus (SLE) is frequently accompanied by neuropsychiatric (NP) and cognitive deficits of unknown etiology. By using autoimmune MRL-lpr mice as an animal model of NP-SLE, we examine the relationship between autoimmunity, hippocampal damage, and behavioral dysfunction. Fluoro Jade B (FJB) staining and anti-ubiquitin (anti-Ub) immunocytochemistry were used to assess neuronal damage in young (asymptomatic) and aged (diseased) mice, while spontaneous alternation behavior (SAB) was used to estimate the severity of hippocampal dysfunction. The causal relationship between autoimmunity and neuropathology was tested by prolonged administration of the immunosuppressive drug cyclophosphamide (CY). In comparison to congenic MRL +/+ controls, SAB acquisition rates and performance in the "reversal" trial were impaired in diseased MRL-lpr mice, suggesting limited use of the spatial learning strategy. FJBpositive neurons and anti-Ub particles were frequent in the CA3 region. Conversely, CY treatment attenuated the SAB deficit and overall FJB staining. Similarly to mouse brain, the hippocampus from a patient who died from NP-SLE showed reduced neuronal density in the CA3 region and dentate gyrus, as well as increased FJB positivity in these regions. Gliosis and neuronal loss were observed in the gray matter, and T lymphocytes and stromal calcifications were common in the choroid plexus. Taken together, these results suggest that systemic autoimmunity induces significant hippocampal damage, which may underlie affective and cognitive deficits in NP-SLE.

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Section: Discussionmentioning

confidence: 99%

Hippocampal damage in mouse and human forms of systemic autoimmune disease

Ballok¹,

Woulfe

Sur

et al. 2004

Hippocampus

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“…In lpr/lpr mice, a mouse model of SLE, a depressive-like phenotype was observed in the forced swim and tail suspension tests and the depressive-like behaviors were shown to be associated with increased levels of IL-6 protein in the hippocampus and prefrontal cortex (Sukoff Rizzo et al, 2012). Increased levels of IL-6 and IL-1β mRNA were observed in the hippocampus and cerebellum of the lpr/lpr mice and correlated with behavioral dysfunction (Tomita et al, 2001a, 2001b). Mice with colon carcinoma cell-induced peripheral tumor showed memory impairment and depression-like behavior in behavioral tests (open field test, tail suspension test and object recognition memory test) and these behaviors were associated with increased levels of IL-6 mRNA in the hippocampus (Yang et al, 2014).…”

Section: Animal Studies Provide Evidence Of Role For Il-6 In Behaviormentioning

confidence: 97%

IL-6 regulation of synaptic function in the CNS

2015

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A growing body of evidence supports a role for glial-produced neuroimmune factors, including the cytokine IL-6, in CNS physiology and pathology. CNS expression of IL-6 has been documented in the normal CNS at low levels and at elevated levels in several neurodegenerative or psychiatric disease states as well as in CNS infection and injury. The altered CNS function associated with these conditions raises the possibility that IL-6 has neuronal or synaptic actions. Studies in in vitro and in vivo models confirmed this possibility and showed that IL-6 can regulate a number of important neuronal and synaptic functions including synaptic transmission and synaptic plasticity, an important cellular mechanism of memory and learning. Behavioral studies in animal models provided further evidence of an important role for IL-6 as a regulator of CNS pathways that are critical to cognitive function. This review summarizes studies that have lead to our current state of knowledge. In spite of the progress that has been made, there is a need for a greater understanding of the physiological and pathophysiological actions of IL-6 in the CNS, the mechanisms underlying these actions, conditions that induce production of IL-6 in the CNS and therapeutic strategies that could ameliorate or promote IL-6 actions.

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“…As well, they are known to alter emotional reactivity and motivated behavior, to provoke sickness behavior clinically and induce impairments in spatial learning experimentally [103,[138][139][140][141][142]. To explore the relationships between cytokines and CNS disease in lupus, the expression of several proinflammatory cytokine genes in the hippocampus of autoimmune MRL-lpr mice was compared [143,144]. 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.…”

Section: Cytokinesmentioning

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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Aberrant cytokine gene expression in the hippocampus in murine systemic lupus erythematosus

Cited by 43 publications

References 18 publications

Hippocampal damage in mouse and human forms of systemic autoimmune disease

Hippocampal damage in mouse and human forms of systemic autoimmune disease

IL-6 regulation of synaptic function in the CNS

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

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