Background Neuropsychiatric manifestations of systemic lupus erythematosus (NPSLE) affect approximately 40% of patients. Lipocalin-2 (LCN2), an acute-phase reactant protein, is an established urinary biomarker in lupus patients. Previous studies using LCN2-deficient mice have demonstrated its role in glial migration and chemokine regulation in the brain. We therefore hypothesized that LCN2 is involved in NPSLE pathogenesis.
Methods We investigated the lupus prone B6.Sle1.Sle3 (Sle1,3) mouse and the effects of LCN2 deficiency on the development of the neuropsychiatric phenotype exhibited by this strain. Sle1,3, B6.LCN2KO, B6, and Sle1,3-LCN2KO mice (6–10 month old; n=5–10/group) underwent comprehensive neurobehavioral assessment, and brains were evaluated by flow cytometry and RNA sequencing.
Results Sle1,3 mice exhibited significant impairment in spatial (p<0.04, figure 1A) and recognition (p<0.02, figure 1B) memory when compared with B6 mice, and these deficits were attenuated in Sle1,3-LCN2KO mice (p<0.001, p<0.02, figure 1A-B). Furthermore, Sle1,3 mice demonstrated anhedonia, and this depression-like behavior was significantly reduced with LCN2 deficiency (p=0.01, figure 1C). Flow cytometry showed a significant increase in brain infiltrating CD8+ T cells in Sle1,3 mice, with a reduction in infiltration in the Sle1,3-LCN2KO strain (p=0.06). Preliminary analysis of RNA sequencing from sorted microglia revealed differential expression of genes between B6 and Sle1,3 mice (figure 1D) and between Sle1,3 and Sle1,3-LCN2KO mice (figure 1E). Moreover, genes involved in cognition and memory that were differentially expressed in Sle1,3 mice were restored to background B6 expression levels in Sle1,3-LCN2KO mice.
Conclusions Our findings establish the Sle1,3 mouse as an NPSLE model and demonstrate that LCN2 deficiency attenuates neurobehavioral deficits and regulates microglial expression of genes essential to NPSLE development.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.