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The temperature negatively regulates the microbicidal activity of macrophages: why do they kill more in hypothermia?

Grant number: 17/13350-0
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): March 01, 2019
Effective date (End): February 28, 2022
Field of knowledge:Biological Sciences - Immunology - Applied Immunology
Principal Investigator:Alexandre Alarcon Steiner
Grantee:Monique Thaís Costa Fonseca
Home Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:18/03418-0 - Hypothermia in Sepsis: causes and consequences, AP.TEM

Abstract

The impact of body temperature on the immune response is underestimated and little understood. This project is based on the unexpected observation that macrophages from rats exhibit higher microbicidal activity when incubated at a temperature corresponding to the regulated form of hypothermia (36.0°C) than those exposed to a temperature corresponding to fever (38, 5°C). On the other hand, neutrophils respond to temperature in the opposite way: they have greater microbicidal activity at 38.5°C. To explain these observations, we propose that phagocytosis, the main process used by macrophages, is the microbicidal mechanism potentiated at 36.0°C while granule secretion, myeloperoxidase (MPO) secretion and the formation of NET's, resources used only by neutrophils, are increased at 38.5°C. To evaluate these aspects, the influence of temperature on each one of these processes will be studied. More specifically, the cells will be incubated at 36.0°C or 38.5°C and the amount of Escherichia coli phagocytized by macrophages and neutrophils will be assessed. The mechanisms of death in the phagolysosome will also be measured: (1) byproducts of reactive oxygen species (ROS) will be measured in macrophages and neutrophils and, (2) expression of the enzyme induced nitric oxide synthase (iNOS) and (3) reactive nitrogen species will be evaluated in macrophages. Other microbicidal mechanisms will also be measured: (1) granule secretion, (2) MPO secretion and (3) NET's release by neutrophils. In addition, it will be verified whether the modulation of the temperature occurs upstream or downstream the phosphorylation of p47phox, the main regulatory protein of the NADPH oxidase complex, which will be overexpressed in macrophages by insertion of a plasmid containing the coding sequence of this protein. Finally, we will use the RNAseq technique to better understand the influence of temperature on the molecular mechanisms involved in the microbicidal activity of macrophages and neutrophils and to identify other unexpected differences in the transcriptome profile of 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)
KOMEGAE, EVILIN N.; FONSECA, MONIQUE T.; CRUZ-MACHADO, SANSERAY DA SILVEIRA; TURATO, WALTER M.; FILGUEIRAS, LUCIANO R.; MARKUS, REGINA P.; STEINER, ALEXANDRE A. Site-Specific Reprogramming of Macrophage Responsiveness to Bacterial Lipopolysaccharide in Obesity. FRONTIERS IN IMMUNOLOGY, v. 10, JUN 28 2019. Web of Science Citations: 0.

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