Atorvastatin restores Lck expression and lipid raft-associated signaling in T cells from patients with systemic lupus erythematosus

EC Jury, DA Isenberg, C Mauri… - The Journal of …, 2006 - journals.aai.org
EC Jury, DA Isenberg, C Mauri, MR Ehrenstein
The Journal of Immunology, 2006journals.aai.org
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 …
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.
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