The Relationship Between Brain Macrophages and Cognitive Dysfunction in Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving genetic and environmental factors culminating in multiple detrimental comorbidities. One such comorbidity is the onset of what is referred to as CNS lupus (NP-SLE). Despite the impact of NP-SLE on health-related quality of life and although numerous mechanisms have been proposed, none can solely account for NP-SLE pathogenesis. We published that expression of NP-SLE-specific disease signatures in tissue-resident macrophages in the brain correlates with the severity of behavioral deficits in two NP-SLE models prior to overt systemic disease. Further, our single-cell RNA sequencing (scRNA-seq) data identify homeostatic and disease-associated states in tissue-resident macrophages of aged control and NP-SLE-prone mice. However, the disease associated macrophage subset in NP-SLE is depleted for genes associated with phagocytosis, which is in contrast to their known phagocytic role in other diseases. We also find that restricted expression of the disease-associated transcriptional program in NP-SLE tissue-resident macrophages corresponds to improved behavioral outcomes in NP-SLE-prone mice following treatment with fingolimod. These discoveries mark the first to implicate this disease-associated tissueresident macrophage subset as a potentially pathogenic population in NP-SLE, which contrasts with their proposed protective role in the literature. We hypothesize that pathogenic disease-associated tissueresident macrophages in the brain are crucial for NP-SLE development and targeting this population may represent a new therapeutic avenue for treating NP-SLE. In Aim 1, we will determine whether tissueresident brain cells or infiltrating immune cells are required for NP-SLE using reciprocal head-shielded bone marrow chimeric mice of WT and NP-SLE-prone donors and recipients. We will test whether blocking transition from the homeostatic state to the disease-associated state via deletion of TREM2 (a critical functional regulator of this population) in tissue-resident macrophages prevents NP-SLE. We will delineate the role that type I interferon (IFN) plays in the development of NP-SLE-like disease by examining the role for the upstream receptor (IFNAR) and downstream signaling protein IFN regulatory factor 5 (IRF5), which have been linked to SLE susceptibility, via deletion of these signaling mediators in tissue-resident macrophages. We identified a cell subset in human cerebrospinal fluid (CSF) that transcriptionally resembles disease-associated tissue-resident macrophages. Moreover, classical monocytes can repopulate a compromised tissue-resident macrophage niche and we see numerical expansion of these cells in NP-SLE models. In Aim 2, we will obtain paired CSF and peripheral blood (PB) from SLE patients with and without NP-SLE for transcriptional profiling of CSF macrophages and PB monocytes to correlate with clinical outcomes. Despite investigation of tissue-resident macrophages in the brain in other disciplines, we will be the first to examine their role in NP-SLE. These data will be invaluable for downstream development of improved diagnostics or targeted therapies.