Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis

Autor(es):Mostrar menos -

Basso, Paulo Jose ^[1] ; Sales-Campos, Helioswilton ^[2] ; Nardini, Viviani ^[2] ; Duarte-Silva, Murillo ^[1] ; Freitas Alves, Vanessa Beatriz ^[2] ; Bonfa, Giuliano ^[1] ; Rodrigues, Cassiano Costa ^[2] ; Ghirotto, Bruno ^[3] ; Lazo Chica, Javier Emilio ^[4] ; Nomizo, Auro ^[2] ; de Barros Cardoso, Cristina Ribeiro ^[2]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Med Ribeirao Preto, Dept Bioquim & Imunol, Ribeirao Preto - Brazil

^[2] Univ Sao Paulo, Fac Ciencias Farmaceut Ribeirao Preto, Dept Anal Clin Toxicol & Bromatol, Ribeirao Preto - Brazil

^[3] Univ Sao Paulo, Inst Ciencias Biomed, Dept Imunol, Sao Paulo - Brazil

^[4] Univ Fed Triangulo Mineiro, Inst Ciencias Biol & Nat, Uberaba - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN IMMUNOLOGY; v. 12, AUG 9 2021.
• Citações Web of Science: 0

Resumo

The current therapeutic options for Inflammatory Bowel Diseases (IBD) are limited. Even using common anti-inflammatory, immunosuppressive or biological therapies, many patients become unresponsive to the treatments, immunosuppressed or unable to restrain secondary infections. Statins are cholesterol-lowering drugs with non-canonical anti-inflammatory properties, whose underlying mechanisms of action still remain poorly understood. Here, we described that in vitro atorvastatin (ATO) treatment was not toxic to splenocytes, constrained cell proliferation and modulated IL-6 and IL-10 production in a dose-dependent manner. Mice exposed to dextran sulfate sodium (DSS) for colitis induction and treated with ATO shifted their immune response from Th17 towards Th2, improved the clinical and histological aspects of intestinal inflammation and reduced the number of circulating leukocytes. Both experimental and in silico analyses revealed that PPAR-alpha expression is reduced in experimental colitis, which was reversed by ATO treatment. While IBD patients also downregulate PPAR-alpha expression, the responsiveness to biological therapy relied on the restoration of PPAR-alpha levels. Indeed, the in vitro and in vivo effects induced by ATO treatment were abrogated in Ppara(-/-) mice or leukocytes. In conclusion, the beneficial effects of ATO in colitis are dependent on PPAR-alpha, which could also be a potential predictive biomarker of therapy responsiveness in IBD. (AU)

• Processo FAPESP: 10/20162-7 - Papel do eixo hipotálamo-pituitária adrenal e glicocorticóides exógenos na modulação da resposta imune na doença inflamatória intestinal
• Beneficiário: Cristina Ribeiro de Barros Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Jovens Pesquisadores
• Processo FAPESP: 17/08651-1 - Efeito imunomodulador de dehidroepiandrosterona (dhea) na resposta imune de pacientes com doença de crohn não responsivos à terapia com anti-tnf
• Beneficiário: Cristina Ribeiro de Barros Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/11042-6 - Avaliação dos efeitos imunomoduladores de estatinas e glicocorticoides na terapêutica da colite experimental
• Beneficiário: Paulo José Basso
• Modalidade de apoio: Bolsas no Brasil - Mestrado
• Processo FAPESP: 21/08404-0 - O receptor de ativação de proliferação de peroxissomo alpha P(PPAR alfa) medeia os efeitos benéficos de atorvastatina na colite experimental
• Beneficiário: Cristina Ribeiro de Barros Cardoso
• Modalidade de apoio: Auxílio à Pesquisa - Publicações científicas - Artigo