Daniel May de Oliveira1,2, Enedina Maria Lobato de Oliveira3, Merari de Fátima Ramires Ferrari4, Patrícia Semedo5, Meire Ioshie Hiyane6, Marcos Antônio Cenedeze7, Alvaro Pacheco-Silva7, Niels Olsen Saraiva Câmara7,6, Jean Pierre Schatzmann Peron8. 1. Neuroimmune Interactions Laboratory, Department of Immunology, University of São Paulo, São Paulo, SP, 05508-900, Brazil. daniel-larissa@hotmail.com. 2. Laboratory for Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Science IV, University of São Paulo (USP), São Paulo, SP, 05508-090, Brazil. daniel-larissa@hotmail.com. 3. Discipline of Clinical Neurology, Federal University of São Paulo UNIFESP, São Paulo, SP, 04023-900, Brazil. 4. Department of Genetics and Evolutive Biology, Biosciences Institute, University of São Paulo (USP), São Paulo, SP, 05508-090, Brazil. 5. Biosciences Institute, University of São Paulo, São Paulo, SP, 05508-900, Brazil. 6. Laboratory for Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Science IV, University of São Paulo (USP), São Paulo, SP, 05508-090, Brazil. 7. Laboratory of Clinical and Experimental Immunology, Nephrology Division, Medicine Department, Federal University of São Paulo UNIFESP, São Paulo, SP, 04023-900, Brazil. 8. Neuroimmune Interactions Laboratory, Department of Immunology, University of São Paulo, São Paulo, SP, 05508-900, Brazil.
Abstract
AIM: Experimental autoimmune encephalomyelitis (EAE) is a CD4(+)-mediated autoimmune pathology of the central nervous system (CNS) that is used as a model for the study of the human neuroinflammatory disease, multiple sclerosis. During the development of EAE, auto-reactive Th1 and Th17 CD4(+) T cells infiltrate the CNS promoting inflammatory cells recruitment, focal inflammation and tissue destruction. In this sense, statins, agents used to lower lipid levels, have recently shown to exert interesting immunomodulatory function. In fact, statins promote a bias towards a Th2 response, which ameliorates the clinical outcome of EAE. Additionally, simvastatin can inhibit Th17 differentiation. However, many other effects exerted on the immune system by statins have yet to be clarified, in particular during neuroinflammation. Thus, the aim of this study was to investigate the effects of simvastatin on the development of experimental autoimmune encephalomyelitis. METHODS: Mice were immunized with MOG(35-55) and EAE severity was assessed daily and scored using a clinical scale. Cytokine secretion by mononuclear cells infiltrating the CNS was evaluated by flow cytometry. RESULTS: Simvastatin (5 mg/kg/day) improved clinical outcome, induced an increase in TGF-β mRNA expression and inhibited IL-6, IL-12p40, IL-12p70, RANTES and MIP-1β secretion (p < 0.05). This was accompanied by a significant decrease in CNS inflammatory mononuclear cell infiltration, with reduced frequencies of both Th1 and Th17 cells. Simvastatin inhibited the proliferation of T lymphocytes co-cultured with primary microglial cells. CONCLUSIONS: Simvastatin treatment promotes EAE clinical amelioration by inhibiting T cell proliferation and CNS infiltration by pathogenic Th1 and Th17 cells.
AIM: Experimental autoimmune encephalomyelitis (EAE) is a CD4(+)-mediated autoimmune pathology of the central nervous system (CNS) that is used as a model for the study of the human neuroinflammatory disease, multiple sclerosis. During the development of EAE, auto-reactive Th1 and Th17 CD4(+) T cells infiltrate the CNS promoting inflammatory cells recruitment, focal inflammation and tissue destruction. In this sense, statins, agents used to lower lipid levels, have recently shown to exert interesting immunomodulatory function. In fact, statins promote a bias towards a Th2 response, which ameliorates the clinical outcome of EAE. Additionally, simvastatin can inhibit Th17 differentiation. However, many other effects exerted on the immune system by statins have yet to be clarified, in particular during neuroinflammation. Thus, the aim of this study was to investigate the effects of simvastatin on the development of experimental autoimmune encephalomyelitis. METHODS:Mice were immunized with MOG(35-55) and EAE severity was assessed daily and scored using a clinical scale. Cytokine secretion by mononuclear cells infiltrating the CNS was evaluated by flow cytometry. RESULTS:Simvastatin (5 mg/kg/day) improved clinical outcome, induced an increase in TGF-β mRNA expression and inhibited IL-6, IL-12p40, IL-12p70, RANTES and MIP-1β secretion (p < 0.05). This was accompanied by a significant decrease in CNS inflammatory mononuclear cell infiltration, with reduced frequencies of both Th1 and Th17 cells. Simvastatin inhibited the proliferation of T lymphocytes co-cultured with primary microglial cells. CONCLUSIONS:Simvastatin treatment promotes EAE clinical amelioration by inhibiting T cell proliferation and CNS infiltration by pathogenic Th1 and Th17 cells.
Authors: Estelle Bettelli; Yijun Carrier; Wenda Gao; Thomas Korn; Terry B Strom; Mohamed Oukka; Howard L Weiner; Vijay K Kuchroo Journal: Nature Date: 2006-04-30 Impact factor: 49.962
Authors: S Brocke; K Gijbels; M Allegretta; I Ferber; C Piercy; T Blankenstein; R Martin; U Utz; N Karin; D Mitchell; T Veromaa; A Waisman; A Gaur; P Conlon; N Ling; P J Fairchild; D C Wraith; A O'Garra; C G Fathman; L Steinman Journal: Nature Date: 1996-01-25 Impact factor: 49.962
Authors: Sawsan Youssef; Olaf Stüve; Juan C Patarroyo; Pedro J Ruiz; Jennifer L Radosevich; Eun Mi Hur; Manuel Bravo; Dennis J Mitchell; Raymond A Sobel; Lawrence Steinman; Scott S Zamvil Journal: Nature Date: 2002-11-07 Impact factor: 49.962
Authors: Olaf Stüve; Sawsan Youssef; Martin S Weber; Stefan Nessler; Hans-Christian von Büdingen; Bernhard Hemmer; Thomas Prod'homme; Raymond A Sobel; Lawrence Steinman; Scott S Zamvil Journal: J Clin Invest Date: 2006-03-16 Impact factor: 14.808
Authors: Atilla Yilmaz; Christine Reiss; Omeima Tantawi; Alexander Weng; Christian Stumpf; Dorette Raaz; Josef Ludwig; Thomas Berger; Alexander Steinkasserer; Werner G Daniel; Christoph D Garlichs Journal: Atherosclerosis Date: 2004-01 Impact factor: 5.162
Authors: Christian Philipp Kamm; Marwan El-Koussy; Sebastian Humpert; Oliver Findling; Ferdinand von Bredow; Yuliya Burren; Guido Schwegler; Dagmar Schött; Filippo Donati; Martin Müller; Norbert Goebels; Felix Müller; Johannes Slotboom; Barbara Tettenborn; Ludwig Kappos; Yvonne Naegelin; Heinrich Paul Mattle Journal: J Neurol Date: 2012-05-09 Impact factor: 4.849