Type I Interferon induction of neuroinflammation mediates neuropsychiatric lupus

Boston Children'S Hospital, Boston MA

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Abstract

ABSTRACT: In addition to peripheral symptoms such as skin and kidney disease, many Lupus patients (60-80%) also develop psychiatric symptoms referred to as neuropsychiatric lupus (NPSLE). Recently, we reported an interferon stimulated gene (ISG) signature in the CNS in a strain of lupus mice (Sle1 yaa) that correlated with a behavior phenotype. Using a novel spacial transcriptomic approach (MERFISH), we found discrete patches of cells in the brain and spinal cord that express elevated levels of ISG. The novel finding not only demonstrates IFN- I triggering of neuroinflammation in the CNS but suggests cell activation by IFN-1 is not random but spacially regulated. The discrete patches of cells include clusters of glia, endothelium and neurons expressing elevated levels of ISG. Single nuc RNA seq of the hippocampus and hindbrain, regions important in the behavior phenotype of Sle1 mice, confirmed an overall interferon signature with subclusters of cells expressing elevated levels of ISG including death pathway related genes (Aw et al BBI 2023). To explain the behavior change in the lupus mice, we postulate that IFN-I is secreted locally by border macrophages and infiltrating macrophages recruited by deposits of autoantibodies and activated complement in the small vessels of the brain. In support of neurotoxicity at the patches, preliminary results from analysis of the merfish and single nuc seq data identifies reduced neuronal cell density relative to adjoining non-patch regions. This proposal will examine the patches for synaptic and neuronal cell loss and test the importance of IFN -I activated microglia and astrocytes in mediating the injury. Moreover, it will identify the source of IFN I and how it enters the CNS. The major gaps in knowledge addressed in this study include: 1) How do microglial and astrocyte gene expression and function change in lupus? 2) Is there a link between microglia and astrocyte dysfunction, neuropsychiatric lupus symptoms, and neuronal cell death and/or synapse loss? 3) Is type I IFN a key factor in promoting CNS dysfunction in lupus and what is the source? Two aims are proposed: Aim 1: Test hypothesis that activation of brain glial cells by type I interferon leads to inappropriate synaptic pruning and behavior change. Aim 2. Identify the source of type I interferon in the CNS of lupus mice.