Simvastatin ameliorates experimental autoimmune encephalomyelitis by inhibiting Th1/Th17 response and cellular infiltration

Author(s)

de Oliveira, Daniel May ^[1] ; Lobato de Oliveira, Enedina Maria ^[2] ; Ramires Ferrari, Merari de Fatima ^[3] ; Semedo, Patricia ^[4] ; Hiyane, Meire Ioshie ^[5] ; Cenedeze, Marcos Antonio ^[6] ; Pacheco-Silva, Alvaro ^[6] ; Saraiva Camara, Niels Olsen ^{[5, 6]} ; Schatzmann Peron, Jean Pierre ^[1]

Affiliation

^[1] Univ Sao Paulo, Dept Immunol, Neuroimmune Interact Lab, BR-05508900 Sao Paulo, SP - Brazil

^[2] Fed Univ Sao Paulo UNIFESP, Discipline Clin Neurol, BR-04023900 Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Biosci Inst, Dept Genet & Evolut Biol, BR-05508090 Sao Paulo, SP - Brazil

^[4] Univ Sao Paulo, Biosci Inst, BR-05508900 Sao Paulo, SP - Brazil

^[5] Univ Sao Paulo, Lab Transplantat Immunobiol, Dept Immunol, Inst Biomed Sci 4, BR-05508090 Sao Paulo, SP - Brazil

^[6] Fed Univ Sao Paulo UNIFESP, Lab Clin & Expt Immunol, Div Nephrol, Dept Med, BR-04023900 Sao Paulo, SP - Brazil

• Document type: Journal article
• Source: INFLAMMOPHARMACOLOGY; v. 23, n. 6, p. 343-354, DEC 2015.
• Web of Science Citations: 11

Abstract

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. 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. Simvastatin (5 mg/kg/day) improved clinical outcome, induced an increase in TGF-beta mRNA expression and inhibited IL-6, IL-12p40, IL-12p70, RANTES and MIP-1 beta 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. Simvastatin treatment promotes EAE clinical amelioration by inhibiting T cell proliferation and CNS infiltration by pathogenic Th1 and Th17 cells. (AU)

• FAPESP's process: 07/07139-3 - The role of heme oxygenase 1 in different renal inflammatory process in experimental animal models
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 12/02270-2 - New cellular, molecular and immunological mechanisms involved in acute and chronic renal injury: the search for new therapeutical approaches
• Grantee: Niels Olsen Saraiva Câmara
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 11/18703-2 - The role of Indoleamine-2,3-dioxigenase and the Triptophan - Kynurenines axis through NMDA receptors over the immune response in the EAE and stroke model
• Grantee: Jean Pierre Schatzmann Peron
• Support Opportunities: Research Grants - Young Investigators Grants