Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin

Abstract

3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase is a critical enzyme in the mevalonate pathway that regulates the biosynthesis of cholesterol as well as isoprenoids that mediate the membrane association of certain GTPases. Blockade of this enzyme by atorvastatin (AT) inhibits the destructive proinflammatory T helper cell (Th)1 response during experimental autoimmune encephalomyelitis and may be beneficial in the treatment of multiple sclerosis and other Th1-mediated autoimmune diseases. Here we present evidence linking specific isoprenoid intermediates of the mevalonate pathway to signaling pathways that regulate T cell autoimmunity. We demonstrate that the isoprenoid geranylgeranyl-pyrophosphate (GGPP) mediates proliferation, whereas both GGPP and its precursor, farnesyl-PP, regulate the Th1 differentiation of myelin-reactive T cells. Depletion of these isoprenoid intermediates in vivo via oral AT administration hindered these T cell responses by decreasing geranylgeranylated RhoA and farnesylated Ras at the plasma membrane. This was associated with reduced extracellular signal–regulated kinase (ERK) and p38 phosphorylation and DNA binding of their cotarget c-fos in response to T cell receptor activation. Inhibition of ERK and p38 mimicked the effects of AT and induced a Th2 cytokine shift. Thus, by connecting isoprenoid availability to regulation of Th1/Th2 fate, we have elucidated a mechanism by which AT may suppress Th1-mediated central nervous system autoimmune disease.

Therapeutic potential of statins in multiple sclerosis: immune modulation, neuroprotection and neurorepair

“…Atorvastatin treatment also reduced CNS infiltration [8], as described previously with lovastatin treatment of an EAE rat model [7]. These effects of atorvastatin on immunomodulation in EAE were mediated by metabolites of the mevalonate pathway [23]. GGPP mediates proliferation, and FPP mediates Th-1 differentiation of myelinreactive T cells via the MAPK pathway [23].…”

“…The reversal of statin-mediated inhibition by mevalonate demonstrates that effects of statins are mediated by inhibition of HMG-CoA reductase. Reversal of the inhibitory effects of statins by FPP or GGPP but not by cholesterol or squalene, and the ability of FPP or GGPP to overcome the inhibition by inhibitors of isoprenyltransferases that transfers isoprenoids to proteins, document the role of isoprenylation in inflammatory diseases [4,17,[23][24][25][26]. Therefore, inhibition of isoprenylation is reported to play a role in the statin-mediated cholesterol-independent pleiotropic effects targeting inflammation and oxidative stress in various disease states, including MS.…”

“…These effects of atorvastatin on immunomodulation in EAE were mediated by metabolites of the mevalonate pathway [23]. GGPP mediates proliferation, and FPP mediates Th-1 differentiation of myelinreactive T cells via the MAPK pathway [23].…”

A large Rab GTPase family in a small GTPase world

“…Interestingly, statin treatment also decreases TCR signaling and these drugs are also used to suppress autoimmune diseases in clinics. [27][28][29] Our results suggest that CRACR2A-a can be an important target of statins due to its high sensitivity toward statin treatment and the unique degradation mechanism after de-prenylation. Therefore, studies on CRACR2A-a can impact translational studies targeting prenylation of G proteins in intracellular signaling for T cell activation.…”

Impact of environmental factors on alloimmunity and transplant fate

“…However, in some studies, other cholesterol-lowering drugs did not improve transplant outcome (27). While improved transplant survival may be related to the ability of statins to lower lipid levels, statins also have immuno modulatory properties that are independent of lipid-lowering effects (28)(29)(30) in monocytes (31)(32)(33)(34)(35)(36)(37)(38)(39) and T cells (33,34,40,41). Indeed, when treated with lipid-lowering agents, mice with normal lipid levels exhibited prolonged transplant survival (26).…”