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Macrophages and T lymphocytes immunometabolism in metabolic and inflammatory diseases

Grant number: 15/15626-8
Support type:Research Grants - Young Investigators Grants
Duration: April 01, 2016 - March 31, 2020
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Pedro Manoel Mendes de Moraes Vieira
Grantee:Pedro Manoel Mendes de Moraes Vieira
Home Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
Associated scholarship(s):18/21018-9 - The role of transcription factor T-bet in adipose tissue macrophages and its implications on insulin resistance induced by obesity, BP.IC
18/07180-8 - Immunometabolism in macrophages and lymphocytes T in inflamatory and metabolic diseases, BP.IC
17/00079-7 - Effects of LXRs receptor activation on systemic metabolic parameters and on the metabolic modulation of resident tissue macrophages of adipose tissue, BP.DR
+ associated scholarships 17/23679-0 - Study of the function of LXRs receptors in the modulation of t CD4 + lymphocytes in vitro and in vivo, BP.MS
16/18031-8 - HIF-1 alpha in metabolic and functional control of adipose tissue resident macrophages from in diabetes induced by obesity, BP.DR
17/06225-5 - Influence of synthetic ([Nle 4, D-Phe7] -±-MSH on microglia metabolism: possible implications on obesity development, BP.MS
17/12848-5 - Studying NKT cell metabolism in obesity and metabolic syndrome, BP.PD
16/23328-0 - Study of the metabolic regulation of macrophages by leptin, BP.DD - associated scholarships

Abstract

The field of Immunometabolism is the new frontier for Immunology as it integrates the historically distinct disciplines of Metabolism and Immunology. The growing interest in Immunometabolism is fueled by the global obesity epidemic and the strong association between inflammation and metabolic disease. Obesity-induced inflammation is a risk factor for several chronic pathologies and diseases. Investigating how the metabolic status of the immune system is altered under obesogenic conditions will provide insight into new mechanisms and therapeutic targets underlying immunometabolic regulation and homeostasis. Central players regulating this metabolic crosstalk include the transcriptions factors HIF-1± (hypoxia induced factor 1±) and LXR (liver X receptor), and the metabolic sensor mTOR (mammalian target of rapamycin), specifically the complex 1 of mTOR characterized by Raptor and the complex 2 by Rictor. These proteins modulate important cellular immune responses and metabolic signaling, thereby affecting the metabolic status of both the host tissue and overall organism. Chronic disease states can affect the function of these proteins (HIF-1±, LXR and mTOR) to shift host cellular function to a new physiologic state. Thus, this proposal hypothesizes that the transcription factors HIF-1± and LXR and metabolic sensor mTOR regulates the metabolism and inflammatory function of macrophages and CD4 T cells, and are dysregulated under chronic obese, inflammatory and compromised metabolic states. The objective is to determine how metabolism regulates the function of tissue resident macrophages and CD4 T cells under both physiologic and inflammatory states. This proposal will be divided into different projects to evaluate the importance of regulating HIF-1±, LXR and mTOR in Immunometabolic homeostasis. HIF-1±Loxp, LXR±Loxp and ²Loxp, RictorLoxp and RaptorLoxp and OBRLoxp mice will be crossed with LysMcre or CD4cre to conditionally knockout these molecules in macrophages and in CD4 T cells, respectively. The immune profile, intrinsic cellular metabolic capacity, and polarization of macrophages and CD4 T cells will be studied in vitro and in vivo. Transgenic mice will be fed a high fat diet to induce obesity, insulin resistance and low-grade systemic inflammation. The inflammatory and metabolic statuses of resident tissue leukocytes, including macrophages from diet-induced obese mice will be determined and compared to lean control mice. We expect that 1) HIF-1± is necessary for the induction of an inflammatory profile in resident tissue macrophages by modulating macrophage metabolism, to subsequently prime systemic effects; 2) activation of LXR will inhibit macrophage activation thereby modifying their cellular metabolism and limiting M1 macrophage polarization to lower adipose tissue inflammation and improve metabolic outcomes; 3) LXR activation will inhibit the differentiation of pro-inflammatory CD4 T cells and, subsequently, have a protective role in inflammatory diseases, such as experimental autoimmune encephalomyelitis (EAE); 4) mTOR activation by hyperleptinemia under obesogenic conditions will promote increased macrophage glycolysis and M1 macrophage polarization; 5) low-grade systemic inflammation will be elevated and immunometabolism will be altered in diet-induced obese mice, increasing the risk and severity of autoimmune diseases such as EAE. Findings from this proposal will focus on the crosstalk between the metabolic and the immune systems to identify intersecting mechanisms underlying pathophysiological conditions including obesity and inflammatory diseases that may reveal promising molecular targets and novel therapeutic applications in humans. (AU)

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)
DOS REIS, LARISSA MENEZES; ADAMOSKI, DOUGLAS; OLIVEIRA SOUZA, RODOLPHO ORNITZ; RODRIGUES ASCENCAO, CAROLLINE FERNANDA; SOUSA DE OLIVEIRA, KRISHINA RATNA; CORREA-DA-SILVA, FELIPE; DE SA PATRONI, FABIO MALTA; DIAS, MARILIA MEIRA; CONSONNI, SILVIO ROBERTO; MENDES DE MORAES-VIEIRA, PEDRO MANOEL; SILBER, ARIEL MARIANO; GOMES DIAS, SANDRA MARTHA. Dual inhibition of glutaminase and carnitine palmitoyltransferase decreases growth and migration of glutaminase inhibition-resistant triple-negative breast cancer cells. Journal of Biological Chemistry, v. 294, n. 24, p. 9342-9357, JUN 14 2019. Web of Science Citations: 0.
CORREA-DA-SILVA, FELIPE; PEREIRA, JESSICA A. S.; DE AGUIAR, CRISTHIANE F.; DE MORAES-VIEIRA, PEDRO M. M. Mitoimmunitywhen mitochondria dictates macrophage function. Cell Biology International, v. 42, n. 6, SI, p. 651-655, JUN 2018. Web of Science Citations: 3.
DA SILVA PEREIRA, JESSICA APARECIDA; DA SILVA, FELIPE CORREA; MENDES DE MORAES-VIEIRA, PEDRO MANOEL. The Impact of Ghrelin in Metabolic Diseases: An Immune Perspective. JOURNAL OF DIABETES RESEARCH, 2017. Web of Science Citations: 4.

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