To understand how neuroinflammation is sustained in the absence of systemic inflammation we have studied a mouse model of neuropsychiatric lupus (NPSLE) which is triggered by the penetration of neurotoxic antibodies into the hippocampus. The subsequent activation of microglia leads to dendritic pruning of hippocampal neurons. This process becomes continuous as the neurons with reduced dendritic arborization secrete HMGB1 which contributes to neuroinflammation through two independent mechanisms. First, it binds NMDA receptors forming a bridge for C1q to decorate synapses to target them for pruning. Second, it activates microglia to secrete C1q. Thus, there is a feed forward loop with activated microglia engaging in dendritic pruning. The resulting neuronal damage leads to increased secretion of HMGB1, which in turn activates microglia. In mice, this inflammatory cycle can be sustained for at least a year. ACE inhibitors, which correct the cognitive deficit in this model, act in part by increasing expression of LAIR-1, an inhibitory receptor for C1q on microglia. This converts C1q from an eat me signal into an immunosuppressive signal.