Interferon-\u03b1 exacerbates neuropsychiatric phenotypes in lupus-prone mice

Jing Zeng,Zhizhong Ye,Nan Shen,Yuanjia Tang,Zhihua Yin,Hong Zou,Ping Zhou,Xinyu Meng,Qinglian Xie

doi:10.1186/s13075-019-1985-9

Abstract

BackgroundNeuropsychiatric 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.MethodsAn intravenous injection of Adv-IFN-α (10 mice, 10 × 109 vp) was administered to the IFN-α-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.ResultsIn this study, we performed a series of behavioural tests to assess the neuropsychiatric phenotypes of IFN-α-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.ConclusionsOur research verified that IFN-α 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.

Highlights

Systemic lupus erythaematosus (SLE) is a complex systemic autoimmune disease characterized by a loss of immune tolerance to self-antigens, resulting in inflammation and severe end-organ damage
Consistent with the literature, in our study, we observed that IFN-α-treated mice exhibited significantly higher levels of anti-Double-stranded DNA (dsDNA) and Antinuclear antibody (ANA) (Fig. 1a, b) as well as increased proteinuria (Additional file 1: Figure S1a) compared to those in control mice (Adv-ctrl-treated mice)
IFN-α treatment resulted in significantly higher levels of anti-P (Fig. 1c), which is associated with SLE-related psychiatric and nephritic manifestations [38]

Summary

Introduction

Systemic lupus erythaematosus (SLE) is a complex systemic autoimmune disease characterized by a loss of immune tolerance to self-antigens, resulting in inflammation and severe end-organ damage. The abnormal activation of the type I interferon (IFN) pathway has received particular attention for its role in the pathogenic mechanisms underlying SLE; the role of this pathway was initially demonstrated by the induction of a signature of IFN inducible genes in human monocytes exposed to SLE sera [6] and further corroborated by gene expression microarray studies of peripheral blood cells in SLE [7,8,9,10]. 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. 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

Methods

Results

Discussion

Conclusion