Lupus autoantibodies initiate a maladaptive equilibrium sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling

Carroll, K.; Mizrachi, M.; Simmons, S.; Toz, B.; Wingard, J.; Tehrani, N.; Zarfeshani, A.; Kello, N.; Kowal, C.; Levin, J. Z.; Volpe, B.; Diamond, B.

doi:10.1101/2023.05.01.538935

bioRxiv · 10.1101/2023.05.01.538935

Lupus autoantibodies initiate a maladaptive equilibrium sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling

Carroll, K.·Mizrachi, M.·Simmons, S.·Toz, B.·Wingard, J.·Tehrani, N.·Zarfeshani, A.·Kello, N.·Kowal, C.·Levin, J. Z.·Volpe, B.·Diamond, B.

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Abstract

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 a significant loss of dendritic arborization in the remaining CA1 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 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.

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Carroll, K., Mizrachi, M., Simmons, S., Toz, B., Wingard, J., Tehrani, N., Zarfeshani, A., Kello, N., Kowal, C., Levin, J. Z., Volpe, B., Diamond, B.. 2023-05-01. Lupus autoantibodies initiate a maladaptive equilibrium sustained by HMGB1:RAGE signaling and reversed by LAIR-1:C1q signaling. https://doi.org/10.1101/2023.05.01.538935

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