Background/Purpose: Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects many end organs including the brain. Despite a prevalence of over 50% in SLE patients depending on the attribution model, neuropsychiatric symptoms of SLE (NPSLE), including anxiety and movement disorders, 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. The cross-talk between infiltrating monocyte-derived macrophages and microglia plays a critical role in directing microglial responses. However, the question remains whether macrophage infiltration precedes NPSLE manifestations. Here, we longitudinally investigate macrophage infiltration into the brain in two models of SLE.

Methods: B6 and SLE-prone B6.Sle1Sle2Sle3 (B6.TC; Jackson #007228) mice underwent a battery of behavioral tasks at 2 months of age. Spleen and cervical lymph nodes were weighed as an indicator of systemic disease from female B6 and B6.TC mice spanning disease progression (n=3-5/timepoint; 2, 5, 8, 11 months of age). At each timepoint, brains 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) for single-cell RNA-seq (10X Genomics 3’ v3.1) in conjunction with cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq); analysis pending. Two additional cohorts of B6 and B6.TC mice were evaluated for brain microglia infiltration and microglial distribution via flow cytometry at 11 months of age. NPSLE-prone CReCOM mice showed behavioral deficits at 3 months of age and underwent longitudinal analyses described above.

Results: Similar to patients with NPSLE, B6.TC mice exhibited heightened anxiety, impaired motor coordination and locomotive deficits compared to control mice, suggesting B6.TC mice are a valid model for NPSLE-associated symptoms. NPSLE-prone mice showed an age-dependent increase in splenomegaly and lymphadenopathy. At 11 months of age, microglia were expanded in NPSLE-prone mice compared to their respective controls, including the recently discovered disease-associated microglia subset associated with neurodegenerative disease. Further, there was an age-dependent increase in the number of brain-infiltrating macrophages in NPSLE-prone mice. However, levels of brain-infiltrating macrophages were comparable to levels in control mice at 2 months of age, indicating that macrophage infiltration occurs between 2 and 5 months of age in NPSLE-prone mice.

Conclusion: As macrophage levels in the brains of NPSLE-prone mice are comparable to control levels at 2 months of age but behavioral deficits occur at 2-3 months of age in NPSLE-prone mice, we provide the first evidence that macrophage infiltration may be a response to NPSLE-like disease incited by brain-intrinsic mechanisms rather than a cause. Future studies will identify the exact timing of macrophage infiltration to define their role as either disease initiators or responders and dissect macrophage heterogeneity during NPSLE progression.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/behavioral-deficits-may-precede-influx-of-brain-infiltrating-macrophages-in-neuropsychiatric-symptoms-of-systemic-lupus-erythematosus/