Lupus autoantibodies initiate a maladaptive homeostasis sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling
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.  This leads to immediate, self-limited excitotoxic death of CA1 pyramidal neurons followed by loss of dendritic arborization in the remaining CA1 pyramidal neurons and impaired spatial memory.  Both microglia and C1q are required for dendritic loss.  Here we show that this pattern of hippocampal injury creates a maladaptive homeostasis 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 homeostasis, 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 homeostasis. Overall design: Microglia of NPSLE-like (DNRAb+), control (DNRAb-), and captopril-treated NPSLE-like (DNRAb+ with Captopril) mice were isolated from the hippocampus by fluorescence-activated cell sorting (FACS) according to CD45 and CD11b signal and analyzed using scRNAseq.