Background/Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune syndrome affecting multiple organs, including the brain. More than 60% of patients experience neuropsychiatric symptoms of SLE (NPSLE) that often occur early in disease and go undiagnosed. Despite the devastating impact of NPSLE on health-related quality of life, the underlying disease mechanisms are unknown. Microglia are the resident innate immune cells in the brain, and accumulating evidence points to microglia as a source of neurotoxic factors that drive neurodegenerative disease. However, very few studies have examined microglia in the context of NPSLE. Here, microglia isolated from two lupus-prone mouse strains with NPSLE-like disease were evaluated at the transcriptional level to ascertain the existence of a common gene signature.

Methods: Mice with caspase 8 flanked by loxP sites (Casp8^fl/fl) were bred to mice expressing Cre under control of the CD11c gene promoter (Cre^CD11c) to generate Cre^CD11cCasp8^fl/fl mice. The bicongenic B6.Sle1.Sle3 (Sle1,3) strain was derived from the introgression of 2 lupus susceptibility loci from the NZM2410 spontaneous SLE model onto non-autoimmune C57BL/6 (B6) mice. Casp8^fl/fl, Cre^CD11cCasp8^fl/fl, B6 and Sle1.3 mice were evaluated for behavioral deficits at 8-10 months of age (n=4/group). Cellular infiltration into the brain was assessed using 10-color flow cytometric analysis. Microglia were sorted for RNA-seq analysis.

Results: We have shown that CD11c-specific deletion of caspase 8, an enzyme in the Fas pathway classically linked to apoptosis initiation and necroptosis suppression, induces an inflammatory disease reminiscent of both human and classic murine models of SLE. Cre^CD11cCasp8^fl/fl mice also exhibit significant impairment in coordination/balance and working memory/learning behaviors similar to patients with SLE. Likewise, the lupus-prone Sle1,3 mouse strain exhibits depression-like behavior and significant impairment in spatial and recognition memory, symptoms detected in SLE patients. In both lupus-prone strains, behavioral deficits correlate with increased leukocyte infiltration including T cells and macrophages. Of the significantly upregulated genes (p<0.05, fold change in expression>1.5) observed in Cre^CD11cCasp8^fl/fl (276) and Sle1,3 (246) microglia compared to their respective controls, 22 genes are shared (p=3.23×10^–5, hypergeometric distribution). These shared genes are involved in ‘cell chemotaxis’ (p=7.99×10^-4; Vcam1, Slamf8, Cxcl16), ‘scavenger receptor activity’ (p=1.27×10^-4; Cxcl16, Lgals3bp), ‘negative regulation of inflammatory response’ (p=1.83×10^-4; ApoE, ApoD, Slamf8), ‘negative regulation of lipid metabolic process’ (p=1.38×10^-4; ApoE, ApoD, Niacr1) and ‘response to external stimulus’ (p=1.31×10^-4; Itgax, Slfn2, ApoE, Axl, Pkd2, Cxcl16, Slamf8).

Conclusion: These data substantiate a common microglial transcriptional signature associated with NPSLE-like disease suggestive of a more regulatory role. In future studies, through examination of other NPSLE models, we will assess the penetrance of this common signature to further interrogate how defective microglial function may incite NPSLE.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/evidence-of-a-common-microglial-signature-in-models-of-neuropsychiatric-symptoms-of-systemic-lupus-erythematosus/