Microglia-dependent synapse loss in type I interferon-mediated lupus.

Area of Science:

• Neuroimmunology
• Autoimmune Diseases
• Systemic Lupus Erythematosus (SLE)

Background:

• Systemic lupus erythematosus (SLE) is an incurable autoimmune disease affecting multiple organs.
• Up to 75% of SLE patients develop central nervous system (CNS) lupus, with unknown underlying mechanisms in most cases.
• Early factors in peripheral autoimmunity may contribute to CNS lupus development.

Purpose of the Study:

• To investigate the role of type I interferon (IFN) signaling in CNS lupus pathogenesis.
• To explore the impact of type I IFN on microglia and synaptic integrity in lupus.
• To provide potential therapeutic targets for CNS lupus.

Main Methods:

• Utilized lupus-prone mouse models to study behavioral phenotypes and synapse loss.
• Investigated the effects of blocking type I IFN signaling.
• Examined microglia activation and synaptic material engulfment.
• Analyzed post-mortem hippocampal brain sections from SLE patients.

Main Results:

• Blocking type I IFN signaling prevented behavioral deficits and synapse loss in lupus-prone mice.
• Type I IFN stimulation induced reactive microglia that engulfed neuronal and synaptic material.
• Increased type I IFN signaling was observed in SLE patient brain samples.

Conclusions:

• Type I IFN signaling drives microglia-dependent synapse loss, contributing to CNS lupus.
• These findings support targeting type I IFN signaling, such as with anifrolumab, for CNS lupus treatment.
• Identified a link between CNS lupus, other CNS diseases, and IFN-driven microglia activity.