Abstract
Abstract Systemic lupus erythematosus (SLE) is an autoimmune disease that leads to clinical pathology across organs, including the central nervous system (CNS). In up to 80% of patients with SLE, CNS manifestations can range from anxiety and fatigue to overt psychosis. While studies have demonstrated a hallmark increase in circulating interferon alpha (IFNα) in the peripheral blood and cerebrospinal fluid, the cellular mechanisms leading to neuropsychiatric lupus (NPSLE) remain unclear (Crow et. al., 2014). Using a mouse model of lupus which expresses an elevated IFNα signature and exhibits behaviors of NPSLE, we found a spatial pattern of interferon-stimulated genes (ISGs) in the brain parenchyma utilizing the multiplexed spatial transcriptomics platform MERFISH (Moffitt et. al., 2016). Guided by unbiased single nucleus sequencing highlighting astrocytes and oligodendrocytes as major glial cells enriched in ISG expression, we hypothesized that this spatial distribution implicates IFNα-driven glial activity against neuron function, thus disrupting regions of the CNS that manifests as NPSLE. We also investigated the role of IFNα on microglia activity and behavior changes using a cell-specific Cremouse model. Further functional assays reveal increased synapse engulfment by microglia upon IFNα activation. Despite waning ISGs levels in the periphery, levels in the brain persist along with behavior severity, pointing to a CNS source of IFNα. This body of work demonstrates how IFNα released locally by glial cells can mediate NPSLE development via disruption of neuron function. Deeper understanding of targetable pathways in IFNα signaling will expand the therapeutic potential of type 1 interferon-driven neuropsychiatric diseases.
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