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Role of the short chain fatty acids and their receptor (GPR43) in the neutrophil death induced by anaerobic bacteria

Grant number: 14/22909-3
Support type:Scholarships in Brazil - Master
Effective date (Start): March 01, 2015
Effective date (End): February 28, 2017
Field of knowledge:Biological Sciences - Immunology - Cellular Immunology
Principal Investigator:Marco Aurélio Ramirez Vinolo
Grantee:Erica Moraes Sernaglia
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated research grant:12/10653-9 - Role of short chain fatty acids and their receptor (GPR43) in the immune response to anaerobic bacteria in vivo and in vitro, AP.JP

Abstract

The bacteria Aggregatibacter actinomycetemcomitans (Aa) is involved in the development of infectious conditions such as periodontitis, abscesses and endocarditis. The destruction of the bacteria depends on the activation, migration and the action of effector cells of innate and adaptive immunity, particularly, neutrophils. These cells act by different mechanisms such as the production of species reactives of oxygen and nitrogen, release of proteases and chelating enzymes, phagocytosis and recruitment of other leukocytes in the elimination of microorganisms and reestablishing of homeostasis. By other way, the bacteria Aa have mechanisms, which prevent their elimination by the immune system, including the release of leukotoxin protein that induces apoptosis of leukocytes. In this context, we aim to investigate whether metabolic products of bacteria, the SCFAs (acetate, propionate and butyrate), which are known to modulate important functions of immune system cells including migration, activation and effector function of neutrophils, have some role in inducing death of neutrophils by Aa. For this, we will carry out experiments with neutrophils isolated from mice and incubated with Aa and SCFAs. Parameters associated with cell death and externalization of phosphatidylserine, membrane integrity, activity of lactate dehydrogenase and caspases (1, 3 and 11) will be measured. Inflammatory cytokines (TNF and IL-1beta) will also be quantified in the supernatant of cultures. In order to investigate possible mechanisms, we will use selective caspase inhibitors and knockout animals for caspase-1 and the SCFAs receptor, GPR43. We will also perform co-cultivation of neutrophils (pre-incubated with bacteria and SCFAs) and macrophages to analyze both macrophages and neutrophils cytokine production. In vivo, we will use the subcutaneous chamber model to induce neutrophil death after inoculation of Aa, in plus or absence of SCFAs. Our hypothesis is that these fatty acids produced in the context of Aa infection modify the survival of neutrophils and therefore the final result of the infection process and the degree of tissue damage associated with it.

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)
GALVAO, IZABELA; TAVARES, LUCIANA P.; CORREA, RENAN O.; FACHI, JOSE LUIS; ROCHA, VITOR MELO; RUNGUE, MARCELA; GARCIA, CRISTIANA C.; CASSALI, GEOVANNI; FERREIRA, CAROLINE M.; MARTINS, FLAVIANO S.; OLIVEIRA, SERGIO C.; MACKAY, CHARLES R.; TEIXEIRA, MAURO M.; VINOLO, MARCO AURELIO R.; VIEIRA, ANGELICA T. The Metabolic Sensor GPR43 Receptor Plays a Role in the Control of Klebsiella Pneumoniae Infection in the Lung. FRONTIERS IN IMMUNOLOGY, v. 9, FEB 20 2018. Web of Science Citations: 7.
VIEIRA, ANGELICA T.; GALVAO, IZABELA; MACIA, LAURENCE M.; SERNAGLIA, ERICA M.; VINOLO, MARCO AURELIO R.; GARCIA, CRISTIANA C.; TAVARES, LUCIANA P.; AMARAL, FLAVIO A.; SOUSA, LIRLANDIA P.; MARTINS, FLAVIANO S.; MACKAY, CHARLES R.; TEIXEIRA, MAURO M. Dietary fiber and the short-chain fatty acid acetate promote resolution of neutrophilic inflammation in a model of gout in mice. Journal of Leukocyte Biology, v. 101, n. 1, p. 275+, JAN 2017. Web of Science Citations: 19.

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