Abstract
Neuropsychiatric manifestations of systemic lupus erythematosus (SLE), specifically cognitive dysfunction and mood disorders, are widely prevalent in SLE patients, and yet poorly understood. TNF-like weak inducer of apoptosis (TWEAK) has previously been implicated in the pathogenesis of neuropsychiatric lupus (NPSLE), and we have recently shown its effects on the transcriptome of the cortex of the lupus-prone mice model MRL/lpr. As the hippocampus is thought to be an important focus of NPSLE processes, we explored the TWEAK-induced transcriptional changes that occur in the hippocampus, and isolated several genes (Dnajc28, Syne2, transthyretin) and pathways (PI3K-AKT, as well as chemokine-signaling and neurotransmission pathways) that are most differentially affected by TWEAK activation. While the functional roles of these genes and pathways within NPSLE need to be further investigated, an interesting link between neuroinflammation and neurodegeneration appears to emerge, which may prove to be a promising novel direction in NPSLE research.
Highlights
Neuropsychiatric Lupus (NPSLE) is one of the most prevalent manifestations of Systemic Lupus Erythematosus (SLE), occurring in up to 80% of lupus patients [1]
By fully exploiting the transcriptomic profiles, the workable experimental data was increased by 16,945 times of what is traditionally used in gene expression studies limited to only the average expression levels
It is assumed that genes that are critical for cell survival and function are highly preserved, and those that are meant to allow for adaptation would display higher relative expression variability (REV)
Summary
Neuropsychiatric Lupus (NPSLE) is one of the most prevalent manifestations of Systemic Lupus Erythematosus (SLE), occurring in up to 80% of lupus patients [1]. The more nebulous manifestations are significantly more prevalent (cognitive dysfunction and mood disorders range from 6.6% to 80%, while acute confusional state and cranial neuropathy affect 0.9–7% of patients [1]), but are more difficult to attribute directly to SLE, partly because they commonly occur regardless of systemic disease activity. Due to their apparent non-inflammatory presentation, cognitive dysfunction and mood disorders are thought to often be related to secondary causes, such as the patients being in a chronic disease state, neuro-affective medication use, or structural brain damage due to cerebrovascular disease, among others. The non-specific nature of many of the NPSLE symptoms, and our current lack of understanding of the underlying processes make the diagnosis challenging, and directed treatment options scarce [6,7]
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