Investigation into the pro-inflammatory properties of TNF-alpha and heme in leukocytes in vitro and in vivo.

• Grant number: 12/22048-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2013
• End date: December 14, 2016
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Nicola Amanda Conran Zorzetto
• Grantee: Angélica Aparecida Antoniellis Silveira
• Host Institution: Centro de Hematologia e Hemoterapia (HEMOCENTRO). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated scholarship(s): 14/23170-1 - An investigation into the pro-inflammatory properties of heme in primary human macrophages, BE.EP.DR

Abstract

During inflammatory responses, neutrophils and other leukocytes adhere to the endothelium, leaving the blood vessels and actively moving towards the inflammatory sites. At present, specific inflammatory mechanisms that operate in the neutrophil adhesive properties have not been completely described. Using a model of neutrophil activation by TNF-±, a potent inflammatory cytokine that induces a significant cell adhesion, we propose to investigate the mechanisms and signaling pathways that mediate this increase in neutrophil adhesion. We will investigate the role of the transcription factor, NFºB, in this mechanism and suggest the hypothesis that cellular proteins called Rho GTPases may be involved in the signaling pathway of these cells after their activation by TNF-±. In parallel with this objective, the effects of simvastatin, a drug class of statins, will be studied, aiming to identify new therapeutic targets for the development of anti-inflammatory agents. Results obtained by our research group suggest that simvastatin can directly inhibit the activation of neutrophils; further studies will be conducted to better understand the effect of this drug on the modulation of the adhesive properties of neutrophils. Accordingly, this study will investigate the signaling pathways involved in the mechanism of neutrophil adhesive under inflammatory conditions. For the development of this work, flow adhesion assays, flow cytometry, assessing the activity of cytoplasmic proteins involved in cytoskeletal changes, ELISA, real time PCR, confocal microscopy and intravital microscopy will be used. We hope that this study will help to better explain the behavior of neutrophils during an established inflammatory process. The knowledge of these signaling pathways may be important for developing therapeutic targets for diseases characterized by vascular inflammation.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

ANTONIELLIS SILVEIRA, ANGELICA APARECIDA; DOMINICAL, VENINA MARCELA; VITAL, DAIANA MORELLI; FERREIRA, JR., WILSON ALVES; MARANHAO COSTA, FABIO TRINDADE; WERNECK, CLAUDIO C.; COSTA, FERNANDO FERREIRA; CONRAN, NICOLA. Attenuation of TNF-induced neutrophil adhesion by simvastatin is associated with the inhibition of Rho-GTPase activity, p50 activity and morphological changes. International Immunopharmacology, v. 58, p. 160-165, MAY 2018. (12/22048-2, 10/19916-7, 14/19173-5)

ANTONIELLIS SILVEIRA, ANGELICA APARECIDA; DOMINICAL, VENINA MARCELA; ALMEIDA, CAMILA BONONI; CHWEIH, HANAN; FERREIRA, JR., WILSON ALVES; VICENTE, CRISTINA PONTES; MARANHAO COSTA, FABIO TRINDADE; WERNECK, CLAUDIO C.; COSTA, FERNANDO FERREIRA; CONRAN, NICOLA. TNF induces neutrophil adhesion via formin-dependent cytoskeletal reorganization and activation of beta-integrin function. Journal of Leukocyte Biology, v. 103, n. 1, p. 87-98, JAN 2018. (12/22048-2, 10/19916-7, 14/19173-5)

SILVEIRA, ANGELICA A. A.; MAHON, OLWYN R.; CUNNINGHAM, CLARE C.; CORR, EMMA M.; MENDONCA, RAFAELA; SAAD, SARA T. O.; COSTA, FERNANDO F.; DUNNE, AISLING; CONRAN, NICOLA. S100A8 acts as an autocrine priming signal for heme-induced human M phi pro-inflammatory responses in hemolytic inflammation. Journal of Leukocyte Biology, v. 106, n. 1, p. 35-43, JUL 2019. (12/22048-2, 14/19173-5, 14/23170-1)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SILVEIRA, Angélica Aparecida Antoniellis. Investigation into the pro-inflammatory properties of TNF-alfa and heme in leukocytes in vitro and in vivo. 2017. Doctoral Thesis - Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas Campinas, SP.