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II-02 Neuropsychiatric lupus is dependent on lipocalin-2
  1. Elise Mike1,
  2. Carla Cuda2,
  3. Hadijat Makinde2,
  4. Harris Perlman2 and
  5. Chaim Putterman1,3
  1. 1Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
  2. 2Division of Rheumatology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
  3. 3Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY, USA


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.

Abstract II-02 Figure 1

Sle1,3 mice exhibit reduced preference for objects in novel position in the object placement test (A) and for novel objects in the object recognition test (B), and these spatial memory (A) and recognition memory (B) deficits are attenuated by LCN2 deficiency. (C) Sle1,3 mice tend to demonstrate anhedonia through lack of preference for saccharin-treated water, and LCN2 deficiency ameliorates this depression-like behavior. Data are shown as mean ±SEM. * p<0.05. Volcano plot demonstrates genes differentially expressed between microglia from BL/6 and Sle1,3 mice (D) and between Sle1,3 mice and Sle1,3-LCN2KO mice (E). Red genes are highly significant genes determined by DEseq2 with a false discovery rate of 10%. Red genes to the right or left of the dashed lines are significant genes with a 3-fold (D) or 2-fold (E) change in expression

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.

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