Background/Purpose: Although the pathogenesis of neuropsychiatric lupus (NPSLE) is not fully understood, neuroinflammation plays a major role in disease. Lipocalin-2, an acute phase reactant protein upregulated in SLE, promotes neuroinflammation through inducing brain barrier disruption, glial activation, and neurotoxicity. In this study, we examined the effects of LCN2 deficiency on the development of neurobehavioral deficits in the lupus-prone B6.Sle1.Sle3 (Sle1,3) mouse strain.

Methods: Sle1,3, Sle1,3-LCN2 knockout (KO), B6.LCN2KO, and B6 mice were evaluated for cognitive dysfunction and depression-like behavior at 7-10 months of age (n=5-10/group). Brains were either paraffin-embedded for immunofluorescence staining, or cortex and hippocampal samples were snap frozen for analysis of gene expression. Indicators of systemic disease, including serum IgG anti-dsDNA titers, spleen weight, and renal pathology were assessed. Brains from a separate cohort of age-matched mice were analyzed by flow cytometry, and CD11b+CD64+CD45-low microglia were sorted for RNA sequencing.

Results:

Sle1,3 mice exhibited significant impairment in spatial and recognition memory when compared with B6 mice, and these deficits were significantly attenuated in Sle1,3-LCN2KO mice. Sle1,3 mice also demonstrated anhedonia (abnormal pleasure seeking behavior), and this depression-like behavior was significantly reduced with LCN2 deficiency. Flow cytometry showed a significant increase in brain infiltrating cells, including CD4+ and CD8+ T cells, that was not reduced with LCN2 deficiency. When compared with B6 mice, Sle1,3 mice exhibited increased anti-dsDNA titers, splenomegaly, and glomerular and tubular pathology, but these findings were not attenuated with LCN2 deficiency. In the hippocampus, there was a significant increase in TUNEL-positive cells in Sle1,3 compared with B6 mice, while apoptosis was reduced in the Sle1,3-LCN2KO mice when compared with Sle1,3 brains. Moreover, Iba-1 staining revealed amoeboid (activated) microglial morphology in Sle1,3 hippocampi but a more ramified (resting) morphology in Sle1,3-LCN2KO mice. RNA sequencing of sorted microglia showed that several genes, upregulated in Sle1,3 mice and involved in inflammation and memory (e.g. Plp1, Mal, and Apod), were normalized in Sle1,3-LCN2KO mice. Additionally, in two large independent human cohorts, patients with NPSLE displayed high cerebrospinal fluid levels of LCN2 compared to healthy controls.

Conclusion: Our findings demonstrate that LCN2 deficiency significantly attenuates neurobehavioral deficits, reduces apoptosis in the brain, and modulates microglia morphology in the Sle1,3 lupus-prone strain. Moreover, LCN2 regulates microglial expression of genes essential to NPSLE development, suggesting LCN2 as a novel therapeutic target.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/neuropsychiatric-systemic-lupus-erythematosus-is-dependent-on-lipocalin-2/