Neuroprotective effect of microglia against impairments of auditory steady-state response induced by anti-P IgG from SLE patients in na\xefve mice

Xuejiao Wang,Yingzhuo Li,Jingyi Xu,Pingting Yang,Zijie Li,Jinhong Li,Ling Qin

doi:10.1186/s12974-020-1716-9

Abstract

ObjectiveAutoantibodies against ribosomal P proteins (anti-P antibodies) are strongly associated with the neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE). The present study was designed to assess whether anti-P antibodies can induce abnormal brain electrical activities in mice and investigate the potential cytopathological mechanism.MethodsAffinity-purified human anti-ribosomal P antibodies were injected intravenously into mice after blood–brain barrier (BBB) disruption. The auditory steady-state response (ASSR) was evaluated based on electroencephalography (EEG) signals in response to 40-Hz click-train stimuli, which were recorded from electrodes implanted in the skull of mice. Immunofluorescence staining was used to examine the morphology and density of neurons and glia in the hippocampus and cortex. The presence of apoptosis in the brain tissues was studied using the TUNEL assay. A PLX3397 diet was used to selectively eliminate microglia from the brains of mice.ResultsCirculating anti-P antibodies caused an enhancement of the ASSR and the activation of microglia through the disrupted BBB, while no obvious neural apoptosis was observed. In contrast, when microglia were depleted, anti-P antibodies induced a serious reduction in the ASSR and neural apoptosis.ConclusionOur study indicates that anti-P antibodies can directly induce the dysfunction of auditory-evoked potentials in the brain and that microglia are involved in the protection of neural activity after the invasion of anti-P antibodies, which could have important implications for NPSLE.

Highlights

Diffuse brain dysfunction without overt brain inflammation frequently occurs in systemic lupus erythematosus (SLE) and might involve pathogenic autoantibodies, especially those against neuronal surface components [1, 2]
One hour after anti-P IgG injection, the auditory steady-state response (ASSR) recorded from each mouse remained unchanged (Fig. 1b, e, and h), indicating that blood– brain barrier (BBB) disruption had no significant effect on ASSR
In vitro experiments showed that anti-P antibodies have the potential to induce neuronal apoptosis as a result of calcium overload [16], we found no detectable neuronal apoptosis in the healthy mice that received transfer of anti-P antibodies into the blood circulation

Summary

Introduction

Diffuse brain dysfunction without overt brain inflammation frequently occurs in systemic lupus erythematosus (SLE) and might involve pathogenic autoantibodies, especially those against neuronal surface components [1, 2]. Previous studies have shown that anti-ribosomal P (antiP) antibodies are associated with neuropsychiatric SLE (NPSLE) [3, 4]. Anti-P antibodies are specific markers for SLE [5] and are detected predominantly in patients during the active phases of SLE [6, 7]. Several animal experiments have been conducted to reveal the pathogenetic roles of anti-P antibodies in the central nervous system (CNS). The results show that the passive transfer of human anti-P antibodies to mice can cause cognitive, emotional, and memory dysfunction [14, 15]. The extent of anti-P antibody-induced dysfunction is dependent on the concentration of these antibodies. This may be attributable to the fact that anti-P antibodies bind

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Conclusion