Microglia orchestrate synaptic and neuronal stripping: Implication in neuropsychiatric lupus

Area of Science:

• Neuroimmunology
• Autoimmune Diseases
• Neuroscience

Background:

• Systemic lupus erythematosus (SLE) is a complex autoimmune disease affecting multiple organs, including the brain, leading to neuropsychiatric lupus (NPSLE).
• Microglial activation is a hallmark of NPSLE, but the precise mechanisms of microglia-mediated neurotoxicity remain unclear.
• Elevated M1-like proinflammatory cytokines are found in the cerebrospinal fluid (CSF) of SLE patients, particularly those with neuropsychiatric symptoms.

Purpose of the Study:

• To investigate the role of microglial activation in the pathogenesis of neuropsychiatric lupus (NPSLE).
• To explore the therapeutic potential of inhibiting microglial activation in a mouse model of lupus.

Main Methods:

• Analysis of cytokine levels in CSF from SLE patients.
• Behavioral testing (anxiety, cognition) in MRL/lpr lupus mice.
• Brain tissue analysis (microglial number, cytokine expression) and RNA sequencing of microglia from lupus mice.
• In vitro and in vivo experiments assessing microglia-induced neurotoxicity.
• Evaluation of tofacitinib treatment effects on NPSLE symptoms and neuropathology in MRL/lpr mice.

Main Results:

• MRL/lpr mice exhibited anxiety-like behaviors and cognitive deficits correlating with increased microglial activation and proinflammatory cytokines.
• RNA sequencing revealed upregulated genes related to phagocytosis and M1 polarization in microglia from lupus mice.
• Activated microglia induced synaptic stripping in vivo and neuronal death in vitro.
• Tofacitinib treatment reduced microglial activation, synaptic/neuronal loss, and behavioral abnormalities in MRL/lpr mice.

Conclusions:

• Classically activated (M1) microglia play a significant role in the pathogenesis of NPSLE.
• Inhibiting microglial activation with drugs like minocycline and tofacitinib presents a promising therapeutic strategy for NPSLE.