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

Author(s):Show less -

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]

Affiliation

^[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

• Document type: Journal article
• Source: FRONTIERS IN IMMUNOLOGY; v. 12, AUG 9 2021.
• Web of Science Citations: 0

Abstract

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)

• FAPESP's process: 10/20162-7 - The role of hypothalamus-pituitary-adrenal (HPA) axis and exogenous glucocorticoids in the modulation of immune response in inflammatory bowel disease
• Grantee: Cristina Ribeiro de Barros Cardoso
• Support Opportunities: Research Grants - Young Investigators Grants
• FAPESP's process: 17/08651-1 - Immunomodulatory effects of dehidroepiandrosterone (DHEA) in the immune response of Crohn's disease patients refractory to anti-TNF treatment
• Grantee: Cristina Ribeiro de Barros Cardoso
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/11042-6 - Evaluation of the immune modulatory effects of statins and glucocorticoids in experimental colitis
• Grantee: Paulo José Basso
• Support Opportunities: Scholarships in Brazil - Master