Cognitive impairment is a frequent manifestation of neuropsychiatric systemic lupus erythematosus (NPSLE), present in up to 80% of patients and leading to a diminished quality of life. We have developed a model of lupus-like cognitive impairment which is initiated when anti-DNA, anti-N-methyl D-aspartate receptor (NMDAR) cross- reactive antibodies, which are present in 30% of SLE patients, penetrate the hippocampus 1 . This leads to immediate, self-limited excitotoxic death of CA1 pyramidal neurons followed by a significant loss of dendritic arborization in the remaining CA1 neurons and impaired spatial memory. Both microglia and C1q are required for dendritic loss 1 . Here we show that this pattern of hippocampal injury creates a maladaptive equilibrium that is sustained for at least one year. It requires HMGB1 secretion by neurons to bind RAGE, a receptor for HMGB1 expressed on microglia, and leads to decreased expression of microglial LAIR-1, an inhibitory receptor for C1q. The angiotensin converting enzyme (ACE) inhibitor captopril, which can restore a healthy equilibrium, microglial quiescence, and intact spatial memory, leads to upregulation of LAIR-1. This paradigm highlights HMGB1:RAGE and C1q:LAIR-1 interactions as pivotal pathways in the microglial–neuronal interplay that defines a physiologic versus a maladaptive equilibrium.
Exposure of hippocampal CA1 pyramidal neurons to DNRAbs results in DNRAb binding to NMDARs, mediating excitotoxic death in 30% of neurons. A maladaptive equilibrium begins as a microglial response to apoptotic neuronal debris and progresses as stressed neurons secrete HMGB1, which activate microglia by binding RAGE. Activated microglia secrete proinflammatory cytokines, Type I IFN, and C1q. The secreted HMGB1 acts as a bridge by binding both NMDARs and C1q, which opsonizes synapses for microglial pruning, resulting in a loss of neuronal dendrite branching and spine density. Captopril treatment mediates microglial upregulation of LAIR-1, which induces quiescence when bound by C1q. This allows for a return to a healthy homeostasis and regrowth of dendritic branches and spines. Image created with Biorender.com.