Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by the presence of anti-nuclear antibodies as well as a broad array of clinical manifestations spanning nearly every organ system. Neuropsychiatric syndromes affect over one half of SLE patients, presenting most commonly as cognitive dysfunction or headache. The pathophysiology of neuropsychiatric lupus is not fully understood; however, a critical mechanism has been identified, which involves passage of inflammatory cytokines and anti-brain antibodies through the blood-brain barrier. We previously developed a mouse model to study the effects of anti-dsDNA antibodies that cross-react with the NMDA receptor (NMDAR), termed DNRAbs, which are present in approximately 30% of SLE patients and whose presence in the CSF is associated with non-focal CNS manifestations of neuropsychiatric lupus. In this mouse model, non-spontaneously autoimmune mice are immunized with DWEYS peptide, a DNA mimotope that elicits production of DNRAb antibodies, which act as positive allosteric modulators of the NMDAR. DNRAbs only enter the brain when the blood-brain barrier is porous; so, we administer LPS, which breaches the blood-brain barrier in the hippocampus. In this model, we discovered two stages of brain injury. In the first stage, lasting up to a week, we observed excitotoxic neuronal death, secondary to DNRAb-mediated NMDAR activation. In the second stage, lasting months, we identified an inflammatory homeostasis, consisting of microglial activation, loss of dendritic arborization in surviving hippocampal neurons, and neuronal secretion of HMGB1, a chromatin protein that can be secreted to act as a damage-associated molecular pattern (DAMP). Once secreted by neurons, HMGB1 interacts with two important receptors -RAGE and TLR4 – inducing a cascade of downstream inflammatory events. In addition, HMGB1 binds to the GluN2B subunit of NMDARs and the complement component C1q, forming a molecular bridge that facilitates synaptic pruning. Here we show that HMGB1 acts directly on microglia, where it activates microglia through RAGE and TLR4 signaling. We found that HMGB1 stimulates microglia to secrete IFNa, transcriptionally upregulating interferon regulatory factors, including IRF7. We also show that IFNa secreted by microglia acts in an autocrine fashion, regulating IFN-response genes such as MX1; IFNa also induces C3 and C1q transcription in microglia. HMGB1 also stimulates microglia to secrete TNFa and IL-1b, which enhances the inflammatory milieu in surrounding neurons. In addition, we found that the ACE-inhibitor captopril reverses dendritic pruning in DWEYS-immunized mice– – an essential component of the second stage of DNRAb-related damage – by regulating expression of the inhibitory receptor LAIR1 in microglia. Whereas captopril reverses dendritic pruning in DWEYS-immunized wildtype mice, captopril has no such effect on LAIR1 knockout mice. We are currently analyzing RNA sequencing data from microglia isolated from captopril-treated, DWEYS immunized mice, to characterize the transcriptional program responsible for this process.