Role of Peroxiredoxins in the differentiation of myeloid leukemia cells and neutrophil function

• Grant number: 17/12312-8
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: September 01, 2017
• End date: August 31, 2022
• Field of knowledge: Biological Sciences - Biochemistry
• Principal Investigator: Flavia Carla Meotti
• Grantee: Luiz Felipe de Souza
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/07937-8 - Redoxome - Redox Processes in Biomedicine, AP.CEPID
• Associated scholarship(s): 18/24333-2 - Role of peroxiredoxins in the differentiation of myeloid leukemia cells and neutrophil function, BE.EP.PD

Abstract

Neutrophils have a major role in the innate immune system. These cells can produce a wide range of cytokines, and therefore are important regulators of inflammatory processes. The high oxidant production during oxidative burst suggest that these cells may have several signaling pathways under redox modulation, but studies focusing on intracellular redox signaling in neutrophils are scarce. The peroxiredoxin (Prx) are a family of efficient thiol peroxidases that play key roles in modulating redox processes in cells, acting as peroxide "sensors". In promyelocytic HL-60 cells differentiated to a neutrophil-like state, we showed that Prx1 is oxidized in response to exposure to Staphylococcus aureus, and that this event was dependent on NADPH oxidase activation. Furthermore, we observed a significant decrease in Prx2 expression upon differentiation. In contrast, both Prx1 and Prx2 in human neutrophils were already oxidized under basal conditions, and stimulation with bacteria or PMA did not affect the redox state of Prx. Knowing that Prx can modulate several cellular functions, such as proliferation and apoptosis, the aim of this study is to investigate the role of Prx1 and Prx2 in the redox control of theses cells. First, we will analyze the contribution of Prx1 and Prx2 to the differentiation of HL-60 cells by knocking down theses enzymes and compare the rates of proliferation, differentiation, and apoptosis. By employing redox proteomics, we will also identify which proteins are being oxidized upon differentiation of HL-60 cells, and how the lack of Prx1 or Prx2 affect the oxidation of these proteins. In neutrophils, we will investigate why the Prx are already oxidized in non-stimulated cells. We will search for interaction partners of Prx under non-stimulated and stimulated conditions to unravel their functions in neutrophil apoptosis and inflammatory response. With this work, we expect to answer important question regarding the redox signaling in neutrophils, and how this signaling can affect the differentiation, function, and apoptosis in these cells.

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)

PESKIN, ALEXANDER V.; MEOTTI, FLAVIA C.; SOUZA, LUIZ F. DE; ANDERSON, ROBERT F.; WINTERBOURN, CHRISTINE C.; SALVADOR, ARMINDO. Intra-dimer cooperativity between the active site cysteines during the oxidation of peroxiredoxin 2. Free Radical Biology and Medicine, v. 158, p. 115-125, OCT 2020. (13/07937-8, 18/14898-2, 17/12312-8)

DE SOUZA, LUIZ F.; PEARSON, ANDREE G.; PACE, PAUL E.; DAFRE, ALCIR L.; HAMPTON, MARK B.; MEOTTI, FLAVIA C.; WINTERBOURN, CHRISTINE C.. Peroxiredoxin expression and redox status in neutrophils and HL-60 cells. Free Radical Biology and Medicine, v. 135, p. 227-234, MAY 1 2019. (17/12312-8, 13/07937-8)