Background/Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune syndrome affecting multiple organs, including the brain. More than 50% 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, underlying disease mechanisms are unknown. Microglia are the resident innate immune cells of the brain; accumulating evidence points to microglia as drivers of neurological conditions ranging from neurodevelopmental (autism) to neurodegenerative (Alzheimer’s disease, chronic pain) disorders. The recently discovered disease-associated microglia (DAM) subset is enriched for lipid metabolism pathways and phagocytosis-related functions. The vast majority of investigations into microglia, particularly DAM, have occurred in neurodegenerative disease models of Alzheimer’s disease, amyotrophic lateral sclerosis and multiple sclerosis. However, very few studies have examined microglia, particularly DAM, in the context of NPSLE. Here, we probed microglia from two NPSLE-prone mouse strains at the transcriptional level to potentially correlate gene signatures with behavioral deficits.

Methods: Mice with caspase 8 flanked by loxP sites (Casp8^fl/fl, WT) were bred to mice expressing Cre under the CD11c gene promoter to generate CReCOM (Caspase-8 Removed CD11c-specific Overactive MyD88) mice. B6.Sle1.Sle3 mice were derived from the introgression of 2 NZM2410-derived susceptibility loci onto non-autoimmune C57BL/6 (B6) mice. 3-4 month old WT and CReCOM mice underwent behavioral testing. Microglia were sorted from mice following behavioral tasks and from 10-12 month old WT, CReCOM, B6 and B6.Sle1.Sle3 mice for RNA-seq analysis (n=4/group).

Results: CReCOM mice develop an inflammatory disease reminiscent of human SLE and exhibit significant impairment in spatial memory, contextual associative learning, startle response and motor coordination, similar to patients with NPSLE. Likewise, the recently validated B6.Sle1Sle3 NPSLE model exhibits depression-like behavior and significant impairment in spatial and recognition memory, symptoms detected in NPSLE patients. Of the significantly upregulated genes (DESeq2, p< 0.05, fold change in expression >1.5) observed in CReCOM (256) and B6.Sle1.Sle3 (214) microglia compared to their respective controls, a common 18-gene ‘NPSLE signature’ is shared (p< 2.54×10-4) and enriched for genes associated with lipid metabolism, scavenger receptor activity and downregulating inflammatory responses and cell chemotaxis processes. NPSLE microglia are also enriched for genes associated with the DAM subset. Moreover, microglial expression of ‘NPSLE’ and ‘DAM’ signatures significantly correlate with the severity of behavioral deficits in CReCOM mice.

Conclusion: The discovery of our novel ‘NPSLE signature’, as well as enrichment of the ‘DAM signature’, represents the first to connect microglia-specific transcriptional signatures with clinical outcomes in NPSLE-like disease. In future studies, we will assess the penetrance of these signatures to further interrogate how defective microglial function may incite NPSLE.

« Back to 2019 ACR/ARP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/microglia-specific-transcriptional-signatures-correlate-with-behavioral-deficits-in-neuropsychiatric-symptoms-of-systemic-lupus-erythematosus/