title: Behavioral Deficits Are Accompanied by Immunological and Neurochemical Changes in a Mouse Model for Neuropsychiatric Lupus (NP-SLE).
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.
authors.affiliation: Lundbeck Research USA, Paramus, NJ 07652, USA. yli@Lundbeck.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Lundbeck Research USA, Paramus, NJ 07652, USA. ares@clin.au.dk.|Translational Neuropsychiatry Unit, Aarhus University, Risskov DK-8240, Denmark. ares@clin.au.dk.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Eskelund
authors.affiliation: Lundbeck Research USA, Paramus, NJ 07652, USA. hzho@Lundbeck.com.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Lundbeck Research USA, Paramus, NJ 07652, USA. dpbu@Lundbeck.com.
authors.forename: David P
authors.initials: DP
authors.lastname: Budac
authors.affiliation: Lundbeck Research USA, Paramus, NJ 07652, USA. cs@lundbeck.com.
authors.forename: Connie
authors.initials: C
authors.lastname: Sánchez
authors.affiliation: Behavioral Core Facility, Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA. maria.gulinello@einstein.yu.edu.
authors.forename: Maria
authors.initials: M
authors.lastname: Gulinello
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000378:metabolism; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D007737:Kynurenine / Q000378:metabolism; D020945:Lupus Vasculitis, Central Nervous System / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D018925:Chemokines; D016207:Cytokines; D007737:Kynurenine
keywords: MRL/lpr; anhedonia; chemokines; cytokines; forced swim test; indoleamine-2,3-dioxygenase (IDO); kynurenine; lupus; novel object placement test