Concurrent Contribution of Both Brain-Intrinsic and Peripheral Disease Mechanisms to Neuropsychiatric Symptoms of Systemic Lupus Erythematosus (NPSLE) 4834

Abstract Description NPSLE are among the least understood of SLE complications, yet increasing evidence points to microglia, a brain-resident innate immune cell population, as a driver of disease. Transfer of BM from CD45.1 donor mice into head-shielded B6.Sle1Sle2Sle3 (TC; CD45.2) host mice reduces SLE-like disease, while reconstitution of CD45.1 hosts with TC BM induces SLE-like disease. As in NPSLE patients, TC mice exhibit heightened anxiety and coordination defects; anxiety persists in chimeric mice of TC, but not CD45.1, host origin, suggesting brain-intrinsic defects in TC mice are required for this behavior. However, impaired coordination in TC mice is recapitulated by both brain-intrinsic and hematopoietic-derived defects in TC mice. CITE-seq data of CD45.1 BM::TC chimeras reveal a persistent increase in disease-associated microglia, macrophages, and T cells of TC host origin despite reconstitution with CD45.1 BM, suggesting these niches are not turning over but are locally expanding and contributing to anxiety and coordination defects. In contrast, TC BM::CD45.1 chimeras show partial replacement of CD45.1 brain-resident macrophages, T cells, and B cells by TC donor cells without expansion, suggesting that aberrantly activated TC-derived macrophages and lymphocytes that initiate localized inflammation, or circulating factors derived from systemic inflammation, contribute to coordination defects. Thus, NPSLE manifestations may diverge in mechanistic origin within the same organism. Funding Sources Supported by NIH NIAID R01 AI170938. Topic Categories Neuroimmunology (NEUR)