Statins Counter the Effects of Hyperlipidemia on iNKT Cells

Abstract

Statins are the most widely used lipid-lowering drugs. Byinhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)reductasetheyblocktherate-limitingstepofcholesterolsynthesis,resultinginup-regulationoflowdensitylipoprotein(LDL) receptors on liver cell membranes, reduced plasmaLDL, and reduced atherosclerosis. In addition to their lipidlowering effects, statins reduce inflammation by effects onmany other cells. These include lymphocyte-suppressingeffects in patients with elevated cholesterol levels [1]. Theanti-inflammatory effects of statins are secondary to HMG-CoA inhibition and result from diminished post-translationalprotein prenylation of small G proteins such as Ras and Rho,which are important signaling molecules that regulate antigenpresenting cells (APCs) and lymphocytes [2]. RhoH hasrecently been shown to serve as an adaptor molecule thatregulates the subcellular localization of the proximal T cellsignaling molecules, lymphocyte-specific protein tyrosinekinase (Lck) and Zeta-chain-associated protein kinase 70(Zap-70) [3](Fig.1).TheantigensthatactivatemostTcellreceptorsarepeptidespresentedbyMHConAPCs.InaminorsubsetoflymphocytesknownasiNKTcells,certainlipidantigensarepresentedbytheMHC-like molecule, CD1d. The TCRs of iNKT cells are notvariable, as is the case for most TCRs, but rather are invariant.Someoftheantigensthat activateiNKTcellsarederivedfromthe membrane lipids of microbes and rapidly activate iNKTcells to provide host defense against infection [ 4]. In addition,antigen presenting cells are stimulated to synthesize endoge-nous glycolipid antigens in response to the activation of Tolllikereceptors(TLRs)onantigenpresentingcells[ 5].AlthoughiNKT cells play a protective role in host defense against mi-crobialinfections,indiseasessuch asatherosclerosis,sicklecellanemia and asthma, iNKTcell activation can be deleterious tothe host [6, 7].In this issue, Nakou et al. [8] demonstrate that hyper-lipidemic individuals have significantly lower numbers ofcirculating iNKT cells than controls. During 6 months oftherapy with 40 mg/day simvastatin, the number of iNKTcells in hyperlipidemic patients increased significantly tonear control levels. The increase in circulating iNKT cellsin the patients receiving simvastatin appeared not to be dueto lipid lowering because there was no relationship betweenplasma lipids or triglycerides and numbers of iNKT cells inblood. Moreover, the response to another lipid loweringdrug, ezetimibe (10 mg/day) was similar to simvastatin inchanging plasma lipid profiles of hyperlipidemic patients, butezetimibefailedtoincreasenumbersofcirculatingiNKTcells.Unlike statins, which inhibit HMG-CoA, ezetimibe inhibitsthe absorption of cholesterol in the small intestine. Nakou etal. conclude that the effect of simvastatin to increase circulat-ing iNKT cells in hyperlipidemic patients is not due to thelipid-lowering effects of the statin.It remains to be determined why simvastatin increases thenumber of circulating iNKT cells in hyperlipidemic patientsandiftheincreaseisofbenefittothepatient.SinceiNKTcellshavebeenshowntoaccelerateatherosclerosisprogression,theincrease in circulating iNKT cells could be viewed as detri-mental. However, if simvastatin inhibits the activation ofiNKT cells it is likely to reduce the ability of these cells toexacerbate plaque inflammation. Nakou et al. used flowcytometry to measure the expression on iNKT cells of theactivation marker, HLA-DR. They found that the percentageof HLA-DR positive iNKTcells in hyperlipidemic patients issignificantly higher than in controls, consistent with greater