Lipid rafts represent a novel therapeutic target in SLE (50.25)

Abstract

Abstract Lipid rafts play a crucial role in T cell receptor (TCR) signaling. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by abnormal TCR signaling. We found that lipid rafts are aggregated on the surface membrane of T cells from lupus-prone MRL/lpr mice. High levels of aggregated lipid rafts could also be reproduced on T cells of normal C57BL/6 mice treated with anti-CD3 plus CD28 antibodies. The aggregated lipid rafts peaked at the age of 6-7 weeks prior to the appearance of disease pathology in MRL/lpr mice. Depletion of lipid rafts with methyl-B-cyclodextrin (MBCD), which is known to disrupt lipid rafts, or atorvastatin, which is known to inhibit cholesterol biosynthesis delayed disease progression, whereas acceleration of their formation with cholera toxin B, which is known to induce lipid raft clustering, promoted disease progression in MRL/lpr mice. The aggregated lipid rafts harbor diverse molecules including TCR signaling, inflammatory, costimulatory, adhesion and Toll-like receptor molecules. Recruited diverse molecules have costimulation to enhance TCR-mediated response and production of IFN-gamma through intact lipid rafts. Further, crosslinking of lipid rafts promoted IFN-gamma production in vitro, a cytokine known to contribute to the expression of SLE pathology in mice. We propose that lipid rafts represent a novel therapeutic target in SLE.