Metabolism in airway epithelium and immune cells during homeostasis and inflammation

• Grant number: 19/02224-0
• Support type: Scholarships abroad - Research Internship - Doctorate
• Effective date (Start): May 20, 2019
• Effective date (End): May 19, 2020
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal researcher: Reinaldo Salomão
• Grantee: Bianca Rodrigues Lima Ferreira
• Supervisor abroad: Tom Van Der Poll
• Home Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Research place: University of Amsterdam (UvA), Netherlands
• Associated to the scholarship: 16/13855-2 - Evaluation of energy and oxidative metabolism in peripheral blood mononuclear cells (PBMC) from septic patients, BP.DR

Abstract

Respiratory tract infections are a major cause of sepsis. Several defense mechanisms are required to protect the airways from harmful events. Those include epithelial cells, as the first barrier, and innate immune cells. Energy metabolism has an important role in the regulation of cellular function, for instance, activated cells switch their metabolism from oxidative phosphorylation to aerobic glycolysis. However depending on the stimuli, different metabolic pathways, e.g., glycolysis and fatty acid oxidation, might be modulated on innate immune cells. Peroxisome proliferator-activated receptor gamma (PPARy) is a nuclear factor involved in this complex metabolic regulation. Preliminary results indicate that glucose metabolism and metabolic modulation by PPARy influence host response during experimental respiratory infection. Hence, we aim to determine the role of glucose and fatty acids metabolism in epithelial and innate immune cells in airways inflammation both in vitro and in vivo. Fluorescent analogues of palmitate and glucose will be used to assess the metabolic preference of epithelial and immune cells by flow cytometry in lungs of healthy or Pseudomonas aeruginosa infected mice. Using PPARy agonist or inhibitor, we will analyze how chemical modulation of cell metabolism affects immune response to P. aeruginosa: bacterial growth, lung inflammation, immune cells populations and cytokines production will be evaluated. In addition, lipidomics and metabolomics will be performed to assess the metabolic state during inflammation of human primary airway epithelial cells and immune cells cultured in vitro. Using compounds labeled with 16C isotope, we will be able to analyze metabolic dynamics of those cells. Understanding how metabolism regulate immune response may provide a potential therapeutic option to improve clinical outcomes during bacterial infections.

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)

RAMIREZ-MORAL, I; YU, X.; BUTLER, J. M.; VAN WEEGHEL, M.; OTTO, N. A.; FERREIRA, B. LIMA; VAN MAELE, L.; SIRARD, J. C.; DE VOS, A. F.; DE JONG, M. D.; et al. mTOR-driven glycolysis governs induction of innate immune responses by bronchial epithelial cells exposed to the bacterial component flagellin. MUCOSAL IMMUNOLOGY, v. 14, n. 3, p. 594-604, MAY 2021. (19/02224-0)

RAMIREZ-MORAL, IVAN; FERREIRA, BIANCA L.; BUTLER, JOE M.; VAN WEEGHEL, MICHEL; OTTO, NATASJA A.; DE VOS, ALEX F.; YU, XIAO; DE JONG, MENNO D.; HOUTKOOPER, RIEKELT H.; VAN DER POLL, TOM. IF-1 alpha Stabilization in Flagellin-Stimulated Human Bronchial Cells Impairs Barrier Functio. ELL, v. 11, n. 3, FEB 2022. (19/02224-0)

RAMIREZ-MORAL, IVAN; FERREIRA, BIANCA LIMA; DE VOS, ALEX F.; VAN DER POLL, TOM. ost-treatment with the PPAR-gamma agonist pioglitazone inhibits inflammation and bacterial growth during Klebsiella pneumoni. RESPIRATORY RESEARCH, v. 22, n. 1, AUG 19 2021. (19/02224-0)