Background/Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune syndrome affecting multiple organs, including the brain. Though 50% of patients may experience neuropsychiatric symptoms (NPSLE), underlying disease mechanisms remain largely unknown. Microglia, the tissue-resident macrophage of the brain, are heterogenous and may be associated with a homeostatic microglia (CD11c^lo) or disease-associated microglia (DAM; CD11c^hi) state, a subset common to Alzheimer’s disease (AD). In AD, DAM co-localize with amyloid-b (Ab) plaques, are enriched for genes involved in lysosomal, lipid metabolism and phagocytic pathways and may play a protective role in the early stages of AD by reducing Ab plaque burden. Our group was the first to show that expression of DAM-associated genes correlates with the severity of hippocampal- and cerebellar-associated behavioral deficits in microglia isolated from two NP-SLE models prior to overt systemic disease. While DAM have been extensively studied in AD, to date no studies have specifically examined DAM in NPSLE.

Methods: FACS-purified CD45^dim/+CD11b⁺ cells from whole brain of 11-12-month-old female WT and NPSLE-prone CReCOM mice (n=1) were analyzed by single-cell RNA-seq (scRNA-seq; 10X Genomics 3’ v3.0). NPSLE-prone MRL^lpr/lpr female mice were intraperitoneally injected at 10 weeks of age with fingolimod, a sphingosine-1-phosphate receptor modulator that reduces microglia activation and improves blood brain barrier integrity, or vehicle control 3 times/week for 4 weeks and underwent behavioral testing. FACSorted bulk CD11c^lo homeostatic microglia and DAM were subjected to the Quantseq 3’ RNA-seq. GO analysis (GOrilla) of treatment-unique genes determined enriched processes.

Results: SingleR designated microglia from merged scRNA-seq data, with cluster-specific genes identifying DAM and a CD11c^lo homeostatic subset in control and CReCOM mice. CReCOM DAM are enriched for genes associated with antigen presentation but depleted for genes associated with phagocytosis, which is in contrast to DAM in AD that are critical for phagocytic functions. Moreover, CReCOM CD11c^lo microglia upregulate genes linked to synapse pruning and phagocytosis, consistent with exacerbated synaptic pruning by microglia in NPSLE models. Fingolimod treatment improved depression and spatial memory issues in MRL^lpr/lpr mice. DAM transition from a CD11c^lo homeostatic microglia state; thus, MRL^lpr/lpr DAM are enriched for DAM-associated genes compared to CD11c^lo microglial counterparts. However, fingolimod treatment restricted expression of DAM-associated genes in DAM and induced a unique signature in DAM enriched for genes linked to behavior- and synapse-related processes.

Conclusion: We find that DAM appear to lack typical functions in NPSLE-like disease and restricted expression of the DAM transcriptional program in NPSLE DAM corresponds to improved behavioral outcomes. Together, these discoveries mark the first to implicate DAM as a potentially pathogenic microglia subset in NPSLE. In future studies, we will explore whether DAM actively participate in the initiation of NPSLE-like disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/disease-associated-microglia-are-implicated-in-neuropsychiatric-manifestations-of-systemic-lupus-erythematosus/