Distinct spatial profile of inflammatory gene expression in the brain of a mouse model of neuropsychiatric lupus

Abstract

Abstract Systemic Lupus Erythematosus (SLE) is an incurable autoimmune disease that results in central nervous system (CNS) involvement in up to 80% of patients, with clinical manifestations ranging from anxiety and fatigue to overt psychosis. However, the mechanisms and cellular components underlying these neuropsychiatric symptoms (NPSLE) remain largely unknown. An elevated type 1 interferon (IFN) 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. To test this hypothesis, we first characterized behavioral phenotypes in the Sle1, Yaa mouse model, and show that these mice exhibit anxiety-like, and fatigue-like behaviors consistent with the major clinical manifestations of NPSLE. To assess the spatial distribution of inflammatory gene expression, we utilized MERFISH (Moffitt et. al., 2016), a multiplexed spatial transcriptomics platform, and observed strikingly distinct patches of interferon stimulated gene (ISG) expression within the subcortical regions of Sle1, Yaa 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. 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.