Background SLE is an incurable autoimmune disease that results in central nervous system (CNS) involvement with clinical manifestations including anxiety and depression. However, the mechanism/s underlying these neuropsychiatric symptoms (NPSLE) remain unknown. An elevated type 1 interferon (IFNa) signature has been commonly observed in SLE patients, particularly within the CNS of NPSLE patients (Crow et al., 2014, Shiozawa et al., 1992). Given the diversity of clinical CNS manifestations, we hypothesized that type 1 interferon-mediated inflammation occurs in spatially distinct regions within the CNS, resulting in differential behavioral outcomes depending on the impacted brain region.
Methods Spatial distribution of inflammatory gene expression in the brain was performed using MERFISH, a multiplexed spatial transcriptomics platform employing a custom set of RNA probes. Cell source and in situ results were validated by RT-PCR, RNA scope and single nucleus sequencing of RNA (sNuc-Seq).
Results Characterization of Sle 1, yaa mice in behavior assays, identified anxiety-like, and fatigue-like behaviors consistent with NPSLE. Notably, the behavior changes correlate with distinct patches of interferon stimulated gene (ISG) expression within the subcortical regions of mouse brains. Preliminary single nucleus sequencing (sNuc-Seq) and in situ hybridization results implicate astrocytes and oligodendrocytes as the major cell classes enriched in these ISG patches.
Conclusions In summary, our results validate a mouse behavioral model of NPSLE, and show spatially distinct regions of ISG expression within the CNS, opening up a new avenue of investigation into the fundamental mechanisms of NPSLE.
Acknowledgements The work was supported by a grant from the NIH R01AR072965.
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