Immunometabolic modulators alleviate vascular dysfunction in mice with systemic lupus erythematosus

Area of Science:

• Immunology
• Cardiovascular Medicine
• Metabolic Research

Background:

• Hypertension (HTN) is a major cardiovascular risk factor in systemic lupus erythematosus (SLE).
• Dysfunctional immune cell metabolism contributes to vascular complications in SLE.
• Targeting immune metabolism may offer therapeutic benefits for vascular protection in SLE.

Purpose of the Study:

• To investigate the vascular protective effects of pharmacological interventions targeting immune cell metabolism in a genetic mouse model of SLE.
• To assess the impact of 2-deoxy-D-glucose (2DG) + metformin (Met) and rapamycin on hypertension and aortic dysfunction in SLE mice.

Main Methods:

• Female NZBWF1 lupus mice were treated with vehicle, 2DG + Met, or rapamycin for 4 weeks.
• NZW/LacJ mice served as controls.
• Assessed splenic immune cell metabolism, vascular function (contraction, relaxation), aortic histology, and immune cell infiltration.

Main Results:

• 2DG + Met inhibited splenic glycolysis and mitochondrial metabolism, enhanced AMP-activated protein kinase (AMPK), and suppressed mammalian target of rapamycin (mTOR) activity.
• This treatment prevented HTN, ameliorated aortic dysfunction, reduced vascular thickening, and decreased aortic Th17 cell infiltration.
• Rapamycin also suppressed mTORC1 activity, reduced Th17 differentiation and infiltration, alleviating vascular oxidative stress and endothelial dysfunction.

Conclusions:

• Pharmacological modulation of immune cell metabolism (2DG + Met, rapamycin) improved vascular abnormalities in SLE mice.
• These interventions mitigated vascular inflammation, fibrosis, and oxidative stress.
• Immune metabolic modulators represent a potential therapeutic strategy for hypertensive SLE patients.