Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors

Abstract

Cognitive impairment occurs in 40-90% of patients with systemic lupus erythematosus (SLE), which is characterized by autoantibodies to nuclear antigens, especially DNA. We discovered that a subset of anti-DNA antibodies, termed DNRAbs, cross reacts with the N-methyl-d-aspartate receptor (NMDAR) and enhances NMDAR signaling. In patients, DNRAb presence associates with spatial memory impairment. In a mouse model, DNRAb-mediated brain pathology proceeds through an acute phase of excitotoxic neuron loss, followed by persistent alteration in neuronal integrity and spatial memory impairment. The latter pathology becomes evident only after DNRAbs are no longer detectable in the brain. Here we investigate the mechanism of long-term neuronal dysfunction mediated by transient exposure to antibody. We show that activated microglia and C1q are critical mediators of neuronal damage. We further show that centrally acting inhibitors of angiotensin-converting enzyme (ACE) can prevent microglial activation and preserve neuronal function and cognitive performance. Thus, ACE inhibition represents a strong candidate for clinical trials aimed at mitigating cognitive dysfunction.

Cognitive Dysfunction in Systemic Lupus Erythematosus: A Case for Initiating Trials

“…In DNRAb + mice, an NMDAR–high mobility group box chromosomal protein 1–C1q complex forms at synapses on neuronal dendrites, targeting them for destruction. C1q knockout DNRAb + mice maintain normal dendritic complexity and spine density following LPS administration , confirming a critical contribution of C1q in DNRAb‐mediated pathology.…”

“…We have shown that angiotensin-converting enzyme (ACE) inhibitors, through their centrally acting effects, reduce microglial activation, prevent loss of dendritic arborization, and prevent spatial memory impairment in DNRAb+ mice (42). Treatment with captopril after onset of microglial activation also restored dendritic arborization and spine density (Figure 3), suggesting that surviving neurons in this model do not experience irreversible damage.…”

“…Among the multiple other cytokines associated with NPSLE, IL‐6 and IL‐8 have the most plausible association with neuronal damage, given their presence in CSF in association with proteins that are indicative of neuronal and astrocytic damage . Other inflammatory mediators, such as TWEAK , CCL2 , myelin‐associated neurite outgrowth inhibitor , matrix metalloproteinase 9 , lipocalin 2 , anti–α‐internexin , and the renin–angiotensin system , are also associated with CD in SLE. TWEAK, a cytokine in the tumor necrosis factor (TNF) family, may be implicated in CD, as memory impairment is ameliorated in TWEAK‐deficient MRL/ lpr mice .…”

Microglia responses to interleukin‐6 and type I interferons in neuroinflammatory disease

“…Of note, these functional properties are similar to those recently identified in IFN‐α‐treated microglia (Li et al, ). It has also recently been demonstrated that microglia mediate pathologic dendritic pruning of hippocampal neurons in an anti‐DNA antibody‐mediated mouse model of CNS lupus (Nestor et al, ). Together, these findings link the response of microglia to IFN‐I to the pathogenesis of CNS lupus in mouse models and may also contribute to disease in patients with CNS lupus.…”

Lupus auto-antibodies act as positive allosteric modulators at NMDA receptors and induce spatial memory deficits

“…LPS-treated mice immunogenized to generate DNRAbs and patient-derived DNRAbs display a gamut of pathologies in the hippocampus: aberrant excitatory signaling, apoptosis, dendritic pruning, and microglial activation 10,11,19 . These mice also display expanded place fields in the hippocampus and defects in spatial memory 2,19 . These studies are essential to defining the pathology of the neuropsychiatric component of SLE, but do not define the specific NMDARs that mediate these effects.…”