Abstract
Neuropsychiatric symptoms of systemic lupus erythematosus (NP-SLE) have been understudied compared to end-organ failure and peripheral pathology. Neuropsychiatric symptoms, particularly affective and cognitive indications, may be among the earliest manifestations of SLE. Among the potential pathophysiological mechanisms responsible for NP-SLE are increased peripheral pro-inflammatory cytokines, subsequent induction of indoleamine-2,3-dioxygenase (IDO) and activation of the kynurenine pathway. In the MRL/MpJ-Faslpr (MRL/lpr) murine model of lupus, depression-like behavior and cognitive dysfunction is evident before significant levels of autoantibody titers and nephritis are present. We examined the behavioral profile of MRL/lpr mice and their congenic controls, a comprehensive plasma cytokine and chemokine profile, and brain levels of serotonin and kynurenine pathway metabolites. Consistent with previous studies, MRL/lpr mice had increased depression-like behavior and visuospatial memory impairment. Plasma levels of different inflammatory molecules (Haptoglobin, interleukin 10 (IL-10), interferon γ-inducible protein 10 (IP-10/CXCL10), lymphotactin, macrophage inhibitory protein 3β (MIP-3β/CCL19), monocyte chemotactic protein 1, 3 and 5 (MCP-1/CCL2, MCP-3/CCL7, MCP-5/CCL12), vascular cell adhesion molecule 1 (VCAM-1), lymphotactin and interferon γ (IFN-γ)) were increased in MRL/lpr mice. In cortex and hippocampus, MRL/lpr mice had increased levels of kynurenine pathway metabolites (kynurenine, 3-hydroxykynurenine, 3-hydroxynthranilic acid and quinolinic acid). Therefore, our study suggests that increased cytokine expression may be critical in the regulation subtle aspects of brain function in NP-SLE via induction of IDO and tryptophan/kynurenine metabolism.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple abnormalities of the immune system, end organ pathology and a high incidence of neuropsychiatric symptoms [1,2], with roughly 40%–70% of SLE patients demonstrating cognitive and/or affective disorders [1]
Even though LPR mice had modestly lower locomotor activity, there was no significant correlation between the total tracklength and the immobility in forced swim test in either genotype and these activity levels were within normal ranges
Behavioral tests in the murine MRL/MpJ-Faslpr (MRL/lpr or LPR) model of neuropsychiatric lupus (NP-SLE) confirmed cognitive deficits and depression-like behavior, concomitant with increased levels of specific cytokines and altered brain metabolites of the indoleamine-2,3-dioxygenase (IDO) pathway, these were not associated with decreased brain levels of tryptophan or serotonin
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multiple abnormalities of the immune system, end organ pathology and a high incidence of neuropsychiatric symptoms [1,2], with roughly 40%–70% of SLE patients demonstrating cognitive and/or affective disorders [1]. Cytokines may increase indoleamine-2,3-dioxygenase (IDO) activity and produce kynurenine metabolites, kynurenic acid and quilnolinic acid, both of which affect glutamatergic transmission. NP-SLE symptoms [3,4,5,6]. Neuropsychiatric and neurocognitive symptoms of systemic lupus erythematosus (NP-SLE). Have been understudied compared to end-organ failure and peripheral pathology. Neuropsychiatric symptoms, affective symptoms, may be among some of the earliest manifestations of SLE [2]
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