Using the Mouse to Model Human Diseases: Cognitive Impairment in Systemic Lupus Erythematosus

Khoury, Lara El; Zarfeshani, Aida; Diamond, Betty

doi:10.3899/jrheum.200410

Cited by 3 publications

(1 citation statement)

References 48 publications

(44 reference statements)

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“…Given the scarcity of NPSLE patient brain and peripheral tissue, animal models are critical for further study of the disease. There are few well-established murine models of NPSLE, and to the best of our knowledge, those that exist do not have existent or wellcharacterized peripheral type 1 interferon signatures (El Khoury et al, 2020;Zhuang et al, 2015a). The disease-accelerated Sle1,Yaa mouse exhibits key SLE pathological characteristics, such as high antinuclear autoantibody titers and severe glomerulonephritis, and has a 50% survival rate at 30 weeks of age (Subramanian et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Spatial enrichment of the type 1 interferon signature in the brain of a neuropsychiatric lupus murine model

Lin

Zhang³

et al. 2023

Preprint

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Among systemic lupus erythematosus (SLE) patients, neuropsychiatric symptoms are highly prevalent, being observed in up to 80% of adult and 95% of pediatric patients. Type 1 interferons, particularly interferon alpha (IFNα), have been implicated in the pathogenesis of SLE and its associated neuropsychiatric symptoms (NPSLE). However, it remains unclear how type 1 interferon signaling in the central nervous system (CNS) might result in neuropsychiatric sequelae. In this study, we validate an NPSLE mouse model and find an elevated peripheral type 1 interferon signature alongside clinically relevant NPSLE symptoms such as anxiety and fatigue. Unbiased single-nucleus sequencing of the hindbrain and hippocampus revealed that interferon-stimulated genes (ISGs) were among the most highly upregulated genes in both regions and that gene pathways involved in cellular interaction and neuronal development were generally repressed among astrocytes, oligodendrocytes, and neurons. Using image-based spatial transcriptomics, we found that the type 1 interferon signature is enriched as spatially distinct patches within the brain parenchyma of these mice. Our results suggest that type 1 interferon in the CNS may play an important mechanistic role in mediating NPSLE behavioral phenotypes by repressing general cellular communication pathways, and that type 1 interferon signaling modulators are a potential therapeutic option for NPSLE.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Spatial enrichment of the type 1 interferon signature in the brain of a neuropsychiatric lupus murine model

Lin

Zhang³

et al. 2023

Preprint

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Spatial enrichment of the type 1 interferon signature in the brain of a neuropsychiatric lupus murine model

Lin

Zhang

et al. 2023

Brain, Behavior, and Immunity

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Microglia activation in the presence of intact blood–brain barrier and disruption of hippocampal neurogenesis via IL-6 and IL-18 mediate early diffuse neuropsychiatric lupus

et al. 2023

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IntroductionInflammatory mediators are detected in the cerebrospinal fluid of systemic lupus erythematosus patients with central nervous system involvement (NPSLE), yet the underlying cellular and molecular mechanisms leading to neuropsychiatric disease remain elusive.MethodsWe performed a comprehensive phenotyping of NZB/W-F1 lupus-prone mice including tests for depression, anxiety and cognition. Immunofluorescence, flow cytometry, RNA-sequencing, qPCR, cytokine quantification and blood–brain barrier (BBB) permeability assays were applied in hippocampal tissue obtained in both prenephritic (3-month-old) and nephritic (6-month-old) lupus mice and matched control strains. Healthy adult hippocampal neural stem cells (hiNSCs) were exposedex vivoto exogenous inflammatory cytokines to assess their effects on proliferation and apoptosis.ResultsAt the prenephritic stage, BBB is intact yet mice exhibit hippocampus-related behavioural deficits recapitulating the human diffuse neuropsychiatric disease. This phenotype is accounted by disrupted hippocampal neurogenesis with hiNSCs exhibiting increased proliferation combined with decreased differentiation and increased apoptosis in combination with microglia activation and increased secretion of proinflammatory cytokines and chemokines. Among these cytokines, IL-6 and IL-18 directly induce apoptosis of adult hiNSCs ex vivo. During the nephritic stage, BBB becomes disrupted which facilitates immune components of peripheral blood, particularly B-cells, to penetrate into the hippocampus further augmenting inflammation with locally increased levels of IL-6, IL-12, IL-18 and IL-23. Of note, an interferon gene signature was observed only at nephritic-stage.ConclusionAn intact BBB with microglial activation disrupting the formation of new neurons within the hippocampus represent early events in NPSLE. Disturbances of the BBB and interferon signature are evident later in the course of the disease.

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Using the Mouse to Model Human Diseases: Cognitive Impairment in Systemic Lupus Erythematosus

Cited by 3 publications

References 48 publications

WITHDRAWN: Spatial enrichment of the type 1 interferon signature in the brain of a neuropsychiatric lupus murine model

WITHDRAWN: Spatial enrichment of the type 1 interferon signature in the brain of a neuropsychiatric lupus murine model

Spatial enrichment of the type 1 interferon signature in the brain of a neuropsychiatric lupus murine model

Microglia activation in the presence of intact blood–brain barrier and disruption of hippocampal neurogenesis via IL-6 and IL-18 mediate early diffuse neuropsychiatric lupus

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