Attenuation of TNF-induced neutrophil adhesion by simvastatin is associated with the inhibition of Rho-GTPase activity, p50 activity and morphological changes

Author(s)

Antoniellis Silveira, Angelica Aparecida ^[1] ; Dominical, Venina Marcela ^{[1, 2]} ; Vital, Daiana Morelli ^[1] ; Ferreira, Jr., Wilson Alves ^[1] ; Maranhao Costa, Fabio Trindade ^[3] ; Werneck, Claudio C. ^[4] ; Costa, Fernando Ferreira ^[1] ; Conran, Nicola ^[1]

Affiliation

^[1] Univ Estadual Campinas, UNICAMP, Sch Med, Hematol & Hemotherapy Ctr, Campinas, SP - Brazil

^[2] NHLBI, Flow Cytometry Core Facil, NIH, Bldg 10, Bethesda, MD 20892 - USA

^[3] Univ Estadual Campinas, UNICAMP, Inst Biol, Lab Trop Dis Prof Dr Luiz Jacintho da Silva, Dept, Campinas, SP - Brazil

^[4] Univ Estadual Campinas, UNICAMP, Inst Biol, Dept Biochem & Tissue Biol, Campinas, SP - Brazil

• Document type: Journal article
• Source: International Immunopharmacology; v. 58, p. 160-165, MAY 2018.
• Web of Science Citations: 1

Abstract

Neutrophil adhesion to the vasculature in response to potent inflammatory stimuli, such as TNF-alpha (TNF), can contribute to atheroprogression amongst other pathophysiological mechanisms. Previous studies have shown that simvastatin, a statin with known pleiotropic anti-inflammatory properties, can partially abrogate the effects of TNF-induced neutrophil adhesion, in association with the modulation of beta(2)-integrin expression. We aimed to further characterize the effects of this statin on neutrophil and leukocyte adhesive mechanisms in vitro and in vivo. A microfluidic assay confirmed the ability of simvastatin to inhibit TNF-induced human neutrophil adhesion to fibronectin ligand under conditions of shear stress, while intravital imaging microscopy demonstrated an abrogation of leukocyte recruitment by simvastatin in the microvasculature of mice that had received a TNF stimulus. This inhibition of neutrophil adhesion was accompanied by the inhibition of TNF-induced RhoA activity in human neutrophils, and alterations in cell morphology and (beta(2)-integrin activity. Additionally, TNF augmented the activity of the p50 NF kappa B subunit in human neutrophils and TNF-induced neutrophil adhesion and beta(2)-integrin activity could be abolished using pharmacological inhibitors of NF kappa B translocation, BAY11-7082 and SC514. Accordingly, the TNF-induced elevation of neutrophil p50 activity was abolished by simvastatin. In conclusion, our data provide further evidence of the ability of simvastatin to inhibit neutrophil adhesive interactions in response to inflammatory stimuli, both in vivo and in vitro. Simvastatin appears to inhibit neutrophil adhesion by interfering in TNF-induced cytoskeletal rearrangements, in association with the inhibition of Rho A activity, NF kappa B translocation and, consequently, beta(2)-integrin activity. (AU)

• FAPESP's process: 12/22048-2 - Investigation into the pro-inflammatory properties of TNF-alpha and heme in leukocytes in vitro and in vivo.
• Grantee: Angélica Aparecida Antoniellis Silveira
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 10/19916-7 - Evaluation on elastic fiber synthesis in cell culture obtained from fibrillin-1 defficient mice: Losartan's effect studies
• Grantee: Claudio Chrysostomo Werneck
• Support Opportunities: Regular Research Grants
• FAPESP's process: 14/19173-5 - Vascular inflammation: pathophysiological mechanisms of induction and pathways of cellular activation
• Grantee: Nicola Amanda Conran Zorzetto
• Support Opportunities: Regular Research Grants