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Interferon-? exacerbates neuropsychiatric phenotypes in lupus-prone mice.

ABSTRACT: BACKGROUND:Neuropsychiatric systemic lupus erythaematosus (NP-SLE) is one of the major manifestations of lupus. However, the mechanisms involved in NP-SLE are still largely unknown. The abnormal activation of the type I IFN signalling pathway is involved in SLE pathogenesis and is linked to NP-SLE, but the effect of IFN-? on NP-SLE encephalopathy has not been systematically studied. METHODS:An intravenous injection of Adv-IFN-? (10 mice, 10?×?109 vp) was administered to the IFN-?-treated group, and Adv-ctrl (10 mice, 10?×?109 vp) (ViGene Biosciences, China) was administered to the control group. Gene expression was determined by real-time quantitative polymerase chain reaction (RT-qPCR). Enzyme-linked immunosorbent assay (ELISA) was used to detect antibodies in the serum, and urinary protein levels were measured with a BCA Protein Assay kit. Haematoxylin-eosin (H&E) and periodic acid-Schiff (PAS)-light green staining were used for kidney histology. The elevated plus-maze test, novelty-suppressed feeding assay, open-field test, tail suspension test, social dominance tube test, three-chamber social interaction test, step-down passive avoidance test and novelty Y-maze task were used to assess behaviour. RESULTS:In this study, we performed a series of behavioural tests to assess the neuropsychiatric phenotypes of IFN-?-treated NZB/NZW F1 mice and found that these mice developed a series of mental disorders such as anxiety-like phenotypes, depression-like phenotypes, deficits in sociability and cognitive impairments, which mimic the neuropsychiatric manifestations of NP-SLE, with a consistent onset and progression. CONCLUSIONS:Our research verified that IFN-? plays a critical role in NP-SLE and provides a comprehensive NP-SLE mouse model for dissecting the mechanisms of NP-SLE and developing novel therapies for intervention.

SUBMITTER: Zeng J

PROVIDER: S-EPMC6724270 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Interferon-α exacerbates neuropsychiatric phenotypes in lupus-prone mice.

Zeng Jing J Meng Xinyu X Zhou Ping P Yin Zhihua Z Xie Qinglian Q Zou Hong H Shen Nan N Ye Zhizhong Z Tang Yuanjia Y

Arthritis research & therapy 20190903 1

<h4>Background</h4>Neuropsychiatric systemic lupus erythaematosus (NP-SLE) is one of the major manifestations of lupus. However, the mechanisms involved in NP-SLE are still largely unknown. The abnormal activation of the type I IFN signalling pathway is involved in SLE pathogenesis and is linked to NP-SLE, but the effect of IFN-α on NP-SLE encephalopathy has not been systematically studied.<h4>Methods</h4>An intravenous injection of Adv-IFN-α (10 mice, 10 × 10<sup>9</sup> vp) was administered to ...[more]

PMID: 31481114

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Project description:Neuropsychiatric lupus (NPSLE), the nervous system presentation of systemic lupus erythematosus (SLE), remains challenging to treat due to its unclear pathogenesis and lack of available targeted therapies. A potential contributor to disease progression is brain tertiary lymphoid structures (TLS); these ectopic lymphoid follicles that can develop tissue-targeted antibodies have recently been described in the MRL/lpr lupus mouse strain, a classic model for studying NPSLE. The brains of MRL/lpr mice show a significant increase of CXCL13, an important chemokine in lymphoid follicle formation and retention that may also play a role in the disease progression of NPSLE. The aim of the present study was to inhibit CXCL13 and examine the effect of this intervention on lymphoid formation and the development of neurobehavioral manifestations in lupus mice. Female MRL/lpr mice were injected with an anti-CXCL13 antibody, an IgG1 isotype-matched antibody, or PBS either three times a week for 12 weeks intraperitoneally (IP) starting at 6-8 weeks of age, or continuously intracerebroventricularly (ICV) with an osmotic pump over a two-week period starting at 15 weeks of age. Cognitive dysfunction and depression-like behavior were assessed at the end of treatment. When treatment was delivered IP, anti-CXCL13 treated mice showed significant improvement in cognitive function when compared to control treated mice. Depression-like behavior was attenuated as well. Furthermore, mice that received anti-CXCL13 by the ICV route showed similar beneficial effects. However, the extent of lymphocyte infiltration into the brain and the general composition of the aggregates were not substantively changed by anti-CXCL13 irrespective of the mode of administration. Nevertheless, analysis of brain gene expression in anti-CXCL13 treated mice showed significant differences in key immunological and neuro-inflammatory pathways that most likely explained the improvement in the behavioral phenotype. Our results indicate that CXCL13 affects the behavioral manifestations in the MRL/lpr strain and is important to the pathogenesis of murine NPSLE, suggesting it as a potential therapeutic target.

Dataset Information

Interferon-? exacerbates neuropsychiatric phenotypes in lupus-prone mice.

Publications

Interferon-α exacerbates neuropsychiatric phenotypes in lupus-prone mice.

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