Macrophage lipid accumulation in the presence of immunosuppressive drugs mycophenolate mofetil and cyclosporin A
Tóm tắt
Mycophenolate (MPA) and cyclosporin A (CsA) are two immunosuppressive agents currently used for the treatment of autoimmune diseases. However, reports regarding their effects on inflammation and lipid handling are controversial. Here, we compare the effect of these two drugs on the expression of proteins involved in cholesterol handling and lipid accumulation in a macrophage cell system utilizing M0, M1 and M2 human macrophages and in murine bone marrow-derived macrophages (BMDM). Differentiated M0, M1 and M2 subsets of THP-1 human macrophages were subjected to various concentrations of either MPA or CsA. Expression of proteins involved in reverse cholesterol transport (ABCA1 and 27-hydroxylase) and scavenger receptors, responsible for uptake of modified lipids (CD36, ScR-A1, CXCL16 and LOX-1), were evaluated by real-time PCR and confirmed with Western blot. DiI-oxidized LDL internalization assay was used to assess foam cell formation. The influence of MPA was also evaluated in BMDM obtained from atherosclerosis-prone transgenic mice, ApoE−/− and ApoE−/−Fas−/−. In M0 macrophages, MPA increased expression of ABCA1 and CXCL16 in a concentration-dependent manner. In M1 THP-1 macrophages, MPA caused a significant increase of 27-hydroxylase mRNA and CD36 and SR-A1 receptor mRNAs. Exposure of M2 macrophages to MPA also stimulated expression of 27-hydroxylase, while downregulating all evaluated scavenger receptors. In contrast, CsA had no impact on cholesterol efflux in M0 and M1 macrophages, but significantly augmented expression of ABCA1 and 27-hydroxylase in M2 macrophages. CsA significantly increased expression of the LOX1 receptor in naïve macrophages, downregulated expression of CD36 and SR-A1 in the M1 subpopulation and upregulated expression of all evaluated scavenger receptors. However, CsA enhanced foam cell transformation in M0 and M2 macrophages, while MPA had no effect on foam cell formation unless used at a high concentration in the M2 subtype. Our results clearly underline the importance of further evaluation of the effects of these drugs when used in atherosclerosis-prone patients with autoimmune or renal disease.
Tài liệu tham khảo
Frostegård J. SLE, atherosclerosis and cardiovascular disease. J Intern Med. 2005;257(6):485–95.
Iaccarino L, Bettio S, Zen M, Nalotto L, Gatto M, Ramonda R, Punzi L, Doria A. Premature coronary heart disease in SLE: can we prevent progression? Lupus. 2013;22(12):1232–42.
Manger K, Kalden JR, Manger B. Cyclosporin A in the treatment of systemic lupus erythematosus: results of an open clinical study. Br J Rheumatol. 1996;35:669–75.
Sahin A. Mycophenolate mofetil in the treatment of systemic lupus erythematosus. Eurasian J Med. 2009;41:180–5.
Glomsda BA, Blaheta RA, Hailer NP. Inhibition of monocyte/endothelial cell interactions and monocyte adhesion molecule expression by the immunosuppressant mycophenolate mofetil. Spinal Cord. 2003;41(11):610–9.
Senda M, DeLustro B, Eugui E, Natsumeda Y. Mycophenolic acid, an inhibitor of IMP dehydrogenase that is also an immunosuppressive agent, suppresses the cytokine-induced nitric oxide production in mouse and rat vascular endothelial cells. Transplantation. 1995;60(10):1143–8.
Xu Y, Lai F, Xu Y, Wu Y, Liu Q, Li N, Wei Y, Feng T, Zheng Z, Jiang W, Yu L, Hong B, Si S. Mycophenolic acid induces ATP-binding cassette transporter A1 (ABCA1) expression through the PPARc-LXRa-ABCA1 pathway. Biochem Biophys Res Commun. 2011;414(4):779–82.
von Vietinghoff S, Koltsova EK, Mestas J, Diehl CJ, Witztum JL, Ley K. Mycophenolate mofetil decreases atherosclerotic lesion size by depression of aortic T-lymphocyte and interleukin-17-mediated macrophage accumulation. J Am Coll Cardiol. 2011;57(21):2194–204.
van Leuven SI, Mendez-Fernandez YV, Wilhelm AJ, Wade NS, Gabriel CL, Kastelein JJ, Stroes ES, Tak PP, Major AS. Mycophenolate mofetil but not atorvastatin attenuates atherosclerosis in lupus-prone LDLr−/− mice. Ann Rheum Dis. 2012;71:408–14.
Richez C, Richards RJ, Duffau P, Weitzner Z, Andry CD, Rifkin IR, Aprahamian T. The effect of mycophenolate mofetil on disease development in the gldapoE(−/−) mouse model of accelerated atherosclerosis and systemic lupus erythematosus. PLoS One. 2013;8(4):e61042.
Romero F, Rodriguez-Iturbe B, Pons H, Parra G, Quiroz Y, Rincon J, Gonzalez L. Mycophenolate mofetil treatment reduces cholesterol-induced atherosclerosis in the rabbit. Atherosclerosis. 2000;152(1):127–33.
Drew AF, Tipping PG. Cyclosporine treatment reduces early atherosclerosis in the cholesterol-fed rabbit. Atherosclerosis. 1995;116(2):181–9.
Zanotti I, Greco D, Lusardi G, Zimetti F, Potì F, Arnaboldi L, et al. Cyclosporine A impairs the macrophage reverse cholesterol transport in mice by reducing sterol fecal excretion. PLoS One. 2013;8(8):e71572.
Zahr N, Arnaud L, Marquet P, Haroche J, Costedoat-Chalumeau N, Hulot JS, Funck-Brentano C, Piette JC, Amoura Z. Mycophenolic acid area under the curve correlates with disease activity in lupus patients treated with mycophenolate mofetil. Arthritis Rheum. 2010;62(7):2047–54. https://doi.org/10.1002/art.27495.
van Leuven SI, van Wijk DF, Volger OL, de Vries JP, van der Loos CM, de Kleijn DV, et al. Mycophenolate mofetil attenuates plaque inflammation in patients with symptomatic carotid artery stenosis. Atherosclerosis. 2010;211(1):231–6. https://doi.org/10.1016/j.atherosclerosis.2010.01.043.
Kiani AK, Petri M, Magder LS. Mycophenolate mofetil (MMF) does not slow the progression of subclinical atherosclerosis in SLE over 2 years. Rheumatol Int. 2012;32(9):2701–5. https://doi.org/10.1007/s00296-011-2048-y.
McMahon MA, Dall’era M, Chakravarty E, Craft JE, Gilkeson GS, Kalunian KC, et al. Mycophenolate Mofetil is not associated with reduced cardiovascular or lupus damage accumulation in a cross-sectional lupus cohort study. Arthritis Rheum. 2013;65(Suppl 10):604. https://doi.org/10.1002/art.2013.65.issue-s10.
Kockx M, Jessup W, Kritharides L. Cyclosporin A and atherosclerosis—cellular pathways in atherogenesis. Pharmacol Ther. 2010;128:106–18.
Kisiel B, Kruszewski R, Juszkiewicz A, et al. Methotrexate, cyclosporine A, and biologics protect against atherosclerosis in rheumatoid arthritis. J Immunol Res. 2015;2015:759610. https://doi.org/10.1155/2015/759610.
Wang X, Hu YC, Zhang RY, Jin DX, Jiang Y, Zhang HN, Cong HL. Effect of cyclosporin A intervention on the immunological mechanisms of coronary heart disease and restenosis. Exp Ther Med. 2016;12(5):3242–8.
Oryoji K, Kiyohara C, Horiuchi T, et al. Reduced carotid intima-media thickness in systemic lupus erythematosus patients treated with cyclosporine A. Mod Rheumatol. 2014;24(1):86–92.
Qin Z. The use of THP-1 cells as a model for mimicking the function and regulation of monocytes and macrophages in the vasculature. Atherosclerosis. 2012;221(1):2–11.
Murray PJ, Allen JE, Biswas SK, Fisher EA, Gilroy DW, Goerdt S, Gordon S, et al. Macrophage activation and polarization: nomenclature and experimental guidelines. J Immunity. 2014;06:008.
Feng X, Li H, Rumbin AA, Wang X, La Cava A, Brechtelsbauer K, Castellani LW, Witztum JL, Lusis AJ, Tsao BP. ApoE−/−Fas−/− C57BL/6 mice: a novel murine model simultaneously exhibits lupus nephritis, atherosclerosis, and osteopenia. J Lipid Res. 2007;48(4):794–805.
Engström A, Erlandsson A, Delbro D, Wijkander J. Conditioned media from macrophages of M1, but not M2 phenotype, inhibit the proliferation of the colon cancer cell lines HT-29 and CACO-2. Int J Oncol. 2014;44(2):385–92.
Martinez FO, Helming L, Milde R, Varin A, Melgert BN, Draijer C, Thomas B, et al. Genetic programs expressed in resting and IL-4 alternatively activated mouse and human macrophages: similarities and differences. Blood. 2013;9:121.
Jager N, Teteloshvili N, Zeebregts C, Westra J, Bijl M. Macrophage folate receptor-β (FR- β) expression in auto-immune inflammatory rheumatic diseases: a forthcoming marker for cardiovascular risk? Autoimmun Rev. 2012;11(9):621–6.
Voloshyna I, Teboul I, Littlefield MJ, Siegart NM, et al. Resveratrol counters systemic lupus erythematosus-associated atherogenicity by normalizing cholesterol efflux. Exp Biol Med. 2016;241(14):1611–9.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-delta delta C(T)) Method. Methods. 2001;25(4):402–8.
Cali JJ, Hsieh C, Francke U, Russell DW. Mutations in the bile acid biosynthetic enzyme sterol 27-hydroxylase underlie cerebrotendinous xanthomatosis. J Biol Chem. 1991;266:7779–83.
Teixeira V, Tam L. Novel insights in systemic lupus erythematosus and atherosclerosis. Front Med. 2018;4:262.
Reiss AB, Anwar K, Merrill JT, Chan ES, Awadallah NW, Cronstein BN, Michael Belmont H, Belilos E, Rosenblum G, Belostocki K, Bonetti L, Hasneen K, Carsons SE. Plasma from systemic lupus patients compromises cholesterol homeostasis: a potential mechanism linking autoimmunity to atherosclerotic cardiovascular disease. Rheumatol Int. 2010;30:591–8.
Voloshyna I, Modayil S, Littlefield MJ, Belilos E, Belostocki K, Bonetti L, Rosenblum G, Carsons SE, Reiss AB. Plasma from rheumatoid arthritis patients promotes pro-atherogenic cholesterol transport gene expression in THP-1 human macrophages. Exp Biol Med (Maywood). 2013;238(10):1192–7. https://doi.org/10.1177/1535370213503262.
Orme J, Mohan C. Macrophage subpopulations in systemic lupus erythematosus. Discov Med. 2012;13(69):151–8.
Li F, Yang Y, Zhu X, Huang L, Xu J. Macrophage polarization modulates development of systemic lupus erythematosus. Cell Physiol Biochem. 2015;37(4):1279–88. https://doi.org/10.1159/000430251.
Han S, Zhuang H, Shumyak S, Wu J, Xie C, Li H, Yang LJ, Reeves WH. Liver X receptor agonist therapy prevents diffuse alveolar hemorrhage in murine lupus by repolarizing macrophages. Front Immunol. 2018;9:135.
Reiss AB, Anwar K, Merrill JT, Chan ES, Awadallah NW, Cronstein BN, Michael Belmont H, Belilos E, Rosenblum G, Belostocki K, Bonetti L, Hasneen K, Carsons SE. Plasma from systemic lupus patients compromises cholesterol homeostasis: a potential mechanism linking autoimmunity to atherosclerotic cardiovascular disease. Rheumatol Int. 2010;30(5):591–8.
Steinbrecher UP. Receptors for oxidized low density lipoprotein. Biochim Biophys Acta. 1999;1436:279–98.
Pirillo A, Catapano AL. Soluble lectin-like oxidized low density lipoprotein receptor-1 as a biochemical marker for atherosclerosis-related diseases. Dis Markers. 2013;35(5):413–8.
Lehrke M, Millington SC, Lefterova M, Cumaranatunge RG, Szapary P, Wilensky R, Rader DJ, Lazar MA, Reilly MP. CXCL16 is a marker of inflammation, atherosclerosis, and acute coronary syndromes in humans. J Am Coll Cardiol. 2007;49(4):442–9.
Moore KJ, Sheedy FJ, Fisher EA. Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol. 2013;13(10):709–21.
Voloshyna I, Reiss AB. The ABC transporters in lipid flux and atherosclerosis. Prog Lipid Res. 2011;50:213–24.
Quinn CM, Jessup W, Wong J, Kritharides L, Brown AJ. Expression and regulation of sterol 27-hydroxylase (CYP27A1) in human macrophages: a role for RXR and PPAR gamma ligands. Biochem J. 2005;385(Pt 3):823–30.
Navaneethan SD, Viswanathan G, Strippoli GFM. Treatment options for proliferative lupus nephritis: an update of clinical trial evidence. Drugs. 2008;68:2095–104.
Chowdhary VR. Broad concepts in management of systemic lupus erythematosus. Mayo Clin Proc. 2017;92(5):744–61.
Germano V, Diamanti AP, Ferlito C, Podestà E, Salemi S, Migliore A, D’Amelio R, Laganà B. Cyclosporine A in the long-term management of systemic lupus erythematosus. J Biol Regul Homeost Agents. 2011;25(3):397–403.
Chighizola CB, Ong VH, Meroni PL. The use of cyclosporine A in rheumatology: a 2016 comprehensive review. Clin Rev Allergy Immunol. 2017;52(3):401–23.
Yang TH, Wu TH, Chang YL, Liao HT, Hsu CC, Tsai CY, Chou YC. Cyclosporine for the treatment of lupus nephritis in patients with systemic lupus erythematosus. Clin Nephrol. 2018;89(4):277–85.
Kasitanon N, Boripatkosol P, Louthrenoo W. Response to combination of mycophenolate mofetil, cyclosporin A and corticosteroid treatment in lupus nephritis patients with persistent proteinuria. Int J Rheum Dis. 2018;21(1):200–7. https://doi.org/10.1111/1756-185X.13152.
Jesus D, Rodrigues M, da Silva JAP, Inês L. Multitarget therapy of mycophenolate mofetil and cyclosporine A for induction treatment of refractory lupus nephritis. Lupus. 2018;27(8):1358–62.
Xu F, Chen ZL, Jin WJ, Xie QD, Shi XH. Ideal therapeutic range of cyclosporine in whole blood in kidney-transplanted patients. Int J Clin Pharmacol Res. 1993;13(4):221–4.
Van Gelder T, Meur YL, Shaw LM, et al. Therapeutic drug monitoring of mycophenolate mofetil in transplantation. Ther Drug Monit. 2006;28(2):145–54.
van Leuven SI, Kastelein JJ, Allison AC, Hayden MR, Stroes ES. Mycophenolate mofetil (MMF): firing at the atherosclerotic plaque from different angles? Cardiovasc Res. 2006;69(2):341–7.
Olejarz W, Bryk D, Zapolska-Downar D. Mycophenolate mofetil—a new atheropreventive drug? Acta Pol Pharm. 2014;71(3):353–61.
Le Goff W, Peng DQ, Settle M, Brubaker G, Morton RE, Smith JD. Cyclosporin A traps ABCA1 at the plasma membrane and inhibits ABCA1-mediated lipid efflux to apolipoprotein A-I. Arterioscler Thromb Vasc Biol. 2004;24(11):2155–61.
Emeson EE, Shen ML. Accelerated atherosclerosis in hyperlipidemic C57BL/6 mice treated with cyclosporin A. Am J Pathol. 1993;142(6):1906–15.
Ditiatkovski M, Neelisetti VN, Cui HL, Malesevic M, Fischer G, Bukrinsky M, Sviridov D. Inhibition of extracellular cyclophilins with cyclosporine analog and development of atherosclerosis in apolipoprotein E-deficient mice. J Pharmacol Exp Ther. 2015;353(3):490–5.
Jin S, Mathis AS, Rosenblatt J, Minko T, Friedman GS, Gioia K, Serur DS, Knipp GT. Insights into cyclosporine A-induced atherosclerotic risk in transplant recipients: macrophage scavenger receptor regulation. Transplantation. 2004;77(4):497–504.
Gueguen Y, Ferrari L, Souidi M, Batt AM, Lutton C, Siest G, Visvikis S. Compared effect of immunosuppressive drugs cyclosporine A and rapamycin on cholesterol homeostasis key enzymes CYP27A1 and HMG-CoA reductase. Basic Clin Pharmacol Toxicol. 2007;100(6):392–7.
Nagao K, Maeda M, Manucat NB, Ueda K. Cyclosporine A and PSC833 inhibit ABCA1 function via direct binding. Biochim Biophys Acta. 2013;1831:398–406.
Wong BX, Kyle RA, Myhill PC, Croft KD, Quinn CM, Jessup W, Yeap BB. Dyslipidemic diabetic serum increases lipid accumulation and expression of stearoyl-CoA desaturase in human macrophages. Lipids. 2011;46(10):931–41.