Pristane induced lupus mice as a model for neuropsychiatric lupus (NPSLE)

Abstract

Background The pristane-induced lupus (PIL) model is a useful tool for studying environmental-related systemic lupus erythematosus (SLE). However, neuropsychiatric manifestations in this model have not been investigated in detail. Because neuropsychiatric lupus (NPSLE) is an important complication of SLE, we investigated the neuropsychiatric symptoms in the PIL mouse model to evaluate its suitability for NPSLE studies. Results PIL mice showed olfactory dysfunction accompanied by an anxiety- and depression-like phenotype at month 2 or 4 after pristane injection. The levels of cytokines (IL-1β, IFN-α, IFN-β, IL-10, IFN-γ, IL-6, TNF-α and IL-17A) and chemokines (CCL2 and CXCL10) in the brain and blood–brain barrier (BBB) permeability increased significantly from week 2 or month 1, and persisted throughout the observed course of the disease. Notably, IgG deposition in the choroid plexus and lateral ventricle wall were observed at month 1 and both astrocytes and microglia were activated. Persistent activation of astrocytes was detected throughout the observed course of the disease, while microglial activation diminished dramatically at month 4. Lipofuscin deposition, a sign of neuronal damage, was detected in cortical and hippocampal neurons from month 4 to 8. Conclusion PIL mice exhibit a series of characteristic behavioral deficits and pathological changes in the brain, and therefore might be suitable for investigating disease pathogenesis and for evaluating potential therapeutic targets for environmental-related NPSLE.

Optogenetic stimulation of basal forebrain cholinergic neurons prevents neuroinflammation and neuropsychiatric manifestations in pristane induced lupus mice

“…To evaluate the effect of optogenetic stimulation of BF cholinergic neurons on brain pathophysiological changes, we examined cytokine expression, IgG deposition and lipofuscin accumulation in the brain by ELISA and immunofluorescence staining. Consistent with our previous results [ 15 ], PIL mice presented significantly increased expression of brain cytokines, including tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), IL-1β and IL-10 (Fig. 4 A).…”

“…The reduction of cytokines may be related to the lessened cytokine entries from peripheral circulation due to the improved BBB leakage, and the reduced local cytokine production following a decreased invasion of inflammatory stimulators. IgG deposition has been observed in the hippocampus of PIL mice [ 17 ], which may result from the impairments of BBB, blood-ventricular barrier and choroid plexus-vascular barrier [ 15 ]. Thus, the reduction of IgG deposition in the choroid plexus and lateral ventricular wall may be attributed to the improved vascular barrier function by BF stimulation.…”

“…Lipofuscin, a product of metabolic imbalance of lipids and metals generally caused by neural oxidative stress, increases with age and pathological processes in CNS [ 36 ]. It has been suggested that lipofuscin participates in the pathogenesis of NPSLE in lupus-prone mice with depression [ 15 , 37 ]. The decrease of lipofuscin deposits may be related to the downregulated expression of brain cytokines, which can induce a reduction in the synthesis of oxidative stress products within neurons.…”

“…The pristane induced lupus (PIL) mouse model, despite its primary focus on replicating peripheral manifestations of SLE, has demonstrated some neurological and behavioral abnormalities resembling NPSLE [ 14 ]. Studies utilizing PIL mice have provided evidence of neuroinflammation in the CNS including overproduction of cytokines and chemokines, downregulation of hippocampal N-methyl-D-aspartate (NMDA) receptor subunits NR2A/2B, BBB leakage, immunoglobulin G (IgG) deposition, activation of glial cells (such as microglia and astrocytes) and lipofuscin accumulation within the brain [ 15 – 17 ]. Thus, the PIL mice are considered a valuable tool for studying NPSLE.…”

SVM-Based Model Combining Patients’ Reported Outcomes and Lymphocyte Phenotypes of Depression in Systemic Lupus Erythematosus

“…At the level of animal models, depressive behavior is spontaneous in MRL/lpr transgenic mice, which is the most common SLE animal model and characterized by the abnormal activation of T and B cells. In addition, pristane-induced lupus mice, which is another useful model for SLE, exhibit a series of neuropsychiatric behavioral deficits and pathological changes in the brain [18]. Furthermore, it was found that the stressinduced metabolic disorder of CD4+ T cells can lead to anxiety-like behavior [19].…”