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

• Grant number: 18/24333-2
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): April 15, 2019
• Effective date (End): April 14, 2020
• Field of knowledge: Biological Sciences - Biochemistry - Metabolism and Bioenergetics
• Principal Investigator: Flavia Carla Meotti
• Grantee: Luiz Felipe de Souza
• Supervisor: Christine Coe Winterbourn
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Research place: University of Otago, New Zealand
• Associated to the scholarship: 17/12312-8 - Role of Peroxiredoxins in the differentiation of myeloid leukemia cells and neutrophil function, BP.PD

Abstract

Neutrophils have a major role in innate immune response. In inflammation, these cells are activated to produce large amount of oxidants and, therefore, might be susceptible to redox signaling control. In spite of that, studies focusing on redox signaling in neutrophils are scarce. The peroxiredoxin (Prx) are a family of efficient thiol peroxidases that play a key role in redox signaling processes, acting as peroxide "sensors". In parallel to the reduction of hydrogen peroxide, some Prx also act as molecular chaperone and thus, their role in controlling cellular process can be broader. By developing this post-doctoral project, we demonstrated that the 2-Cys peroxiredoxin 1 (Prx1) and peroxiredoxin 2 (Prx2) are down-regulated in during human leukemic-60 (HL-60) differentiation to neutrophil. Interestingly, both Prx1 and Prx2 were fully oxidized under basal conditions in peripheral blood neutrophils. Therefore, we hypothesized that both Prx1 and Prx2 might have a key role in differentiation and/or proliferation of promyelocytic cells and might have an alternative function, another than hydrogen peroxide reduction, in neutrophils. These Prxs might also be important in apoptosis in the short living neutrophil. Therefore, this project focuses on the contribution of Prx1 and Prx2 into the differentiation of HL-60 cells. To address this hypothesis, Prx1 and Prx2 will be knocked down to compare rates of proliferation, differentiation and apoptosis in HL-60. Relevantly, Prof.'s Winterbourn group has already performed the knockdown of these proteins in Jurkat cells. It also intends to investigate the role of these proteins in neutrophils function and survival. Using redox proteomics, we will search for different pattern of protein oxidation during HL-60 differentiation to identify which pathways are being modulated in this process. In purified blood neutrophils, the partners for Prx under non-stimulated and stimulated conditions will be searched to understand their functions in neutrophil apoptosis and inflammatory response. By developing this project, we expect to answer important questions regarding the redox signaling driving promyelocytic cell differentiation and neutrophils function. Because Prxs are being purposed as targets to treat leukemia, the exactly role of these proteins in white blood cells must be revealed. (AU)