Background/Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multipe end organs, including the brain. Despite a prevalence of over 50% in SLE patients depending on the attribution model, neuropsychiatric symptoms of SLE (NPSLE) are among the least understood complications. Notwithstanding the paucity of data examining underlying mechanisms, accumulating evidence points to microglia, the resident innate immune cells in the brain, as a driver of disease. Microglia are a heterogenous population and may exist as a homeostatic microglia or disease-associated microglia (DAM) state, the latter of which are associated with Alzheimer’s disease (AD). In AD, DAM co-localize with amyloid-b (Ab) plaques 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 microglial expression of DAM-associated genes correlates with the severity of hippocampal- and cerebellar-associated behavioral deficits in a NPSLE model prior to overt systemic disease. While DAM have been extensively studied in AD, to date no studies have specifically examined DAM in NPSLE.

Methods: Separate cohorts of female B6 and SLE-prone B6.Sle1Sle2Sle3 (B6.TC; Jackson #007228) mice underwent a battery of behavioral tasks at 2 months of age and ¹⁸F-FEPPA PET imaging targeting mitochondrial translocator protein-18 kDa (TSPO) in activated microglia at 11 months of age. Brains from additional cohorts were perfused and extracted, meninges were removed and live CD45⁺CD11b⁺ cells were FACSorted from pooled cell suspensions (n=3/strain/timepoint to account for biological variability; 2, 5, 8 and 11 months of age) for cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq; 10X Genomics 3′ v3.1). Data were analyzed in R using the Seurat package. Post-filtering, 10-12K cells/strain/timepoint were maintained.

Results: Similar to patients with NPSLE, B6.TC mice exhibit heightened anxiety and impaired motor learning indicative of amygdalar and cerebellar defects, respectively. We find that DAM in young B6.TC mice are enriched for genes involved in the response to IFN-γ. Activation of microglia by IFN-γ induces proinflammatory T cell-related chemokine genes as well as genes involved in antigen presentation; as a result, signals for T cell infiltration and antigen presentation are produced to allow for microglia-T cell interactions. Indeed, with age, B6.TC DAM expand and not only maintain enrichment of genes associated with the response to IFN-γ, but also adopt expression of genes involved in CD8 T cell activation and antigen presentation via MHC I and MHC II. Upregulation of Tspo expression in aged B6.TC DAM corresponds to increased ¹⁸F-FEPPA uptake in affected brain regions of B6.TC mice, suggesting regional microglial activation.

Conclusion: We find that DAM are somehow primed for activation early in NPSLE-like disease. With age, DAM expand and adopt a more activated phenotype, particularly suited for T cell interactions. Together, these discoveries are among the first to implicate DAM as a potentially pathogenic microglia subset in NPSLE. Future studies will investigate the initial source of IFN-γ.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/age-dependent-expansion-and-activation-of-disease-associated-microglia-in-neuropsychiatric-symptoms-of-systemic-lupus-erythematosus/