Atorvastatin Restores Lck Expression and Lipid Raft-Associated Signaling in T Cells from Patients with Systemic Lupus Erythematosus

Abstract

Loss of tolerance to self-Ags in patients with systemic lupus erythematosus (SLE), a prototypic autoimmune disease, is associated with dysregulation of T cell signaling, including the depletion of total levels of lymphocyte-specific protein kinase (Lck) from sphingolipid-cholesterol-enriched membrane microdomains (lipid rafts). Inhibitors of 3-hyroxy-3-methylgluteryl CoA reductase (statins) can modify the composition of lipid rafts, resulting in alteration of T cell signaling. In this study, we show that atorvastatin targets the distribution of signaling molecules in T cells from SLE patients, by disrupting the colocalization of total Lck and CD45 within lipid rafts, leading to a reduction in the active form of Lck. Upon T cell activation using anti-CD3/anti-CD28 in vitro, the rapid recruitment of total Lck to the immunological synapse was inhibited by atorvastatin, whereas ERK phosphorylation, which is decreased in SLE T cells, was reconstituted. Furthermore, atorvastatin reduced the production of IL-10 and IL-6 by T cells, implicated in the pathogenesis of SLE. Thus, atorvastatin reversed many of the signaling defects characteristic of SLE T cells. These findings demonstrate the potential for atorvastatin to target lipid raft–associated signaling abnormalities in autoreactive T cells and provide a rationale for its use in therapy of autoimmune disease.

Lowering Glycosphingolipid Levels in CD4+ T Cells Attenuates T Cell Receptor Signaling, Cytokine Production, and Differentiation to the Th17 Lineage

“…These observations infer that the composition and dynamics of lipid rafts might contribute to the abnormal T cell behavior in systemic lupus erythematosus (23,24). A subsequent study showing that treatment with atorvastatin can restore Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus, presumably by lowering lipid levels, further supports this notion (25). The role of GSLs in TCR signaling and T cell activation has also been studied using inhibitors of GSL biosynthesis.…”

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

“…T cells from patients with SLE are characterised by alterations in the localisation of membrane signalling molecule that can influence their function [14,18,36]. Therefore, we examined the location of CTLA-4 in relation to lipid microdomains by confocal microscopy.…”

A new approach to the molecular analysis of docking, priming, and regulated membrane fusion

“…We use this system to test the hypothesis that specific lipidic components of the membrane matrix selectively affect the mechanisms underlying vesicle docking, priming, and particularly fast, Ca 2+ -triggered membrane fusion. We used (a) simvastatin (Smst) and atorvastatin (Atst), inhibiting 3-hydroxy-3-methylglutarylcoenzyme A (HMG-CoA) conversion to mevalonate in cholesterol (CHOL) biosynthesis [11,45,48]; (b) zaragozic acid (Zara), suppressing squalene synthase activity and thus farnesyl pyrophosphate conversion to squalene [6,77]; (c) D609, inhibiting phosphatidylcholine (PC) hydrolysis to diacylglycerol by phospholipase C (PLC) [60]; and (d) wortmannin (Wrt) and LY294002 (LY29), inhibiting phosphatidylinositol-3-kinase (PI-3K) activity and hence phosphorylation of polyphosphoinositides (PIP) at the third hydroxyl group, altering production of phosphatidylinositol-3-phosphate (PI(3)P), phosphatidylinositol-(3,4)-bisphosphate (PI(3,4)P2), and phosphatidylinositol-(3,4,5)-trisphosphate (PI(3,4,5)P3) [91,94]. Isolated CSC and/or CV were then quantitatively assessed for molecular alterations and effects on Ca 2+ -triggered fusion.…”