Pitavastatin ameliorates autoimmune neuroinflammation by regulating the Treg/Th17 cell balance through inhibition of mevalonate metabolism

Author(s)

Prado, D. S. ^{[1, 2]} ; Damasceno, L. E. A. ^{[1, 2]} ; Sonego, A. B. ^[1] ; Rosa, M. H. ^{[1, 2]} ; Martins, T. V. ^{[1, 2]} ; Fonseca, M. D. M. ^[1] ; Cunha, T. M. ^{[1, 2]} ; Cunha, F. Q. ^{[1, 2]} ; Alves-Filho, J. C. ^{[1, 2]}

Affiliation

^[1] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Pharmacol, Ave Bandeirantes 3900, BR-14049900 Ribeirao Preto, SP - Brazil

^[2] Univ Sao Paulo, Ribeir ao Preto Med Sch, CRID, Ctr Res Inflammatory Dis, Ribeirao Preto, SP - Brazil

• Document type: Journal article
• Source: International Immunopharmacology; v. 91, FEB 2021.
• Web of Science Citations: 0

Abstract

While Treg cells are responsible for self-tolerance and immune homeostasis, pathogenic autoreactive Th17 cells produce pro-inflammatory cytokines that lead to tissue damage associated with autoimmunity, as observed in multiple sclerosis. Therefore, the immunological balance between Th17 and Treg cells may represent a promising option for immune therapy. Statin drugs are used to treat dyslipidemia; however, besides their effects on preventing cardiovascular diseases, statins also have anti-inflammatory effects. Here, we investigated the role of pitavastatin on experimental autoimmune encephalomyelitis (EAE) and the differentiation of Treg and Th17 cells. EAE was induced by immunizing C57BL/6 mice with MOG35-55. EAE severity was determined by analyzing the clinical score and inflammatory parameters in the spinal cord. Naive CD4 T cells were cultured under Treg and Th17-skewing conditions in vitro in the presence of pitavastatin. We found that pitavastatin decreased EAE development, which was accompanied by a reduction of all parameters investigated. Pitavastatin also reduced the expression of IBA1 and pSTAT3 (Y705 and S727) in the spinal cords of EAE mice. Interestingly, the reduction of Th17 cell frequency in the draining lymph nodes of EAE mice treated with pitavastatin was followed by an increase of Treg cells. Indeed, pitavastatin directly affects T cell differentiation in vitro by decreasing Th17 and increasing Treg cell differentiation. Mechanistically, pitavastatin effects are dependent on mevalonate synthesis. Thus, our data show the potential anti-inflammatory effect of pitavastatin on the pathogenesis of the experimental neuroinflammation by modulating the Th17/Treg axis. (AU)

• FAPESP's process: 16/05377-3 - Role of Erk5 pathway on Th17 and Treg cells differentiation and on experimental autoimmune encephalomyelitis
• Grantee: Douglas da Silva Prado
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 13/08216-2 - CRID - Center for Research in Inflammatory Diseases
• Grantee: Fernando de Queiroz Cunha
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC