# Type I interferon-dependent mechanisms of synapse loss in lupus

> **NIH NIH R01** · BOSTON CHILDREN'S HOSPITAL · 2022 · $461,727

## Abstract

Abstract
Systemic lupus erythematosus is an incurable autoimmune disease characterized by pathogenic
autoantibodies that potentiate inflammatory injury in tissues such as skin, lungs and kidneys. Lupus patients
also experience neurologic symptoms that range from severe headache and seizures to neuropsychosis and
are collectively referred to as CNS Lupus. We propose that neurologic symtoms result from peripheral
interferon alpha that enters the brain and activates the microglia and complement -dependent pruning pathway
leading to synapse loss in brain regions involved in cognition, spatial memory and social behavior. Studies in
murine models of lupus suggest that peripheral immune cells and autoantibody may penetrate the blood brain
barrier and induce pathology. However, in lupus patients symptoms of neuropsychosis are often detected
early in disease suggesting that other factors might be involved in injury without destruction of the blood brain
barrier. In our own study using a murine model of lupus, preliminary results identify an age-dependent
significant increase in the frequency of activated microglia that are positive for uptake of neuronal synaptic
material. Remarkably, the lupus mice develop changes in behavior that correlate with synapse loss. The
pattern of microglia activation and synaptic pruning is similar to that observed during early neural development
where selective synapse elimination is normal. Notably, treatment of the lupus mice in vivo with anti-interferon
receptor antibody was protective. The objective of this proposal is to test our hypothesis that peripheral
cytokines such as type I interferon trigger a microglia-dependent synaptic pruning program leading to
increased elimination of synapses that could explain the neurological symptoms observed in lupus. The
following two aims are proposed.
Specific aim 1: Test the hypothesis that microglia-mediated synaptic pruning becomes activated in
SLE. Based on our preliminary data, we predict that microglia-dependent synapse loss occurs in SLE mouse
models and that activation of the classical complement cascade is required for this process.
Specific aim 2: Test the hypothesis that increased type I interferon signaling in SLE promotes CNS
dysfunction We predict that type I interferon-stimulated microglia activate a synapse pruning gene program
leading to inappropriate engulfment of neuronal material and development of cognitive and social dysfunction.
Moreover, preliminary results suggest that treatment with anti-IFNAR may be protective and prevent synapse
loss.

## Key facts

- **NIH application ID:** 10433932
- **Project number:** 5R01AR072965-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** Michael Craig Carroll
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $461,727
- **Award type:** 5
- **Project period:** 2018-07-16 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433932

## Citation

> US National Institutes of Health, RePORTER application 10433932, Type I interferon-dependent mechanisms of synapse loss in lupus (5R01AR072965-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10433932. Licensed CC0.

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