RANKL system in TLR4 signaling pathway

• Grant number: 16/00508-2
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): March 01, 2016
• Effective date (End): February 29, 2020
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Mariana Kiomy Osako
• Grantee: Ryerson Fonseca Mota
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 14/11092-6 - RANKL system in phenotypic switch of macrophages in adipose tissue inflammation, AP.JP

Abstract

Adipose tissue inflammation is consigned as the responsible source of diabetes mellitus type 2 (T2DM) development. High fat diet and energetic imbalance raise the mass of hypertrophied adipocytes, which release free fatty acids recognized by macrophages and activate the toll like-4 (TLR4) pathway and synthesis of pro-inflammatory cytokines. In this inflammatory microenvironment, adipocytes show lack of insulin pathway activation necessary for glucose uptake, leading to hyperinsulinemia and hyperglycemia. Therefore, insulin resistance in adipose tissue is one of the primary events for T2DM genesis. Osteoprotegerin (OPG) is a decoy receptor of the RANKL protein, which, after binding to it, inhibits activation of its legitimate receptor RANK. High plasma level of OPG has been associated with T2DM and other diseases, however, until this day there is no biological explanation for its increase and pathological development. In our studies, we demonstrate RANKL system in the contribution of vascular calcification and macrophage and microglia activation in ischemic brain, inhibiting the pro-inflammatory (M1) phenotype of these cells. Recent evidence in literature suggests that this system is an important regulator of macrophages in inflammatory responses to septic shock, though the molecular mechanism remains broadly unknown.In this direct doctoral project we propose to clarify the molecular mechanisms that regulate macrophage activation through the RANKL system and its role in macrophage polarization between pro and anti-inflammatory states (M1 and M2 respectively) existent in adipose tissue inflammation, focusing on the activation of the receptor TLR4 in cellular models and mice treated with high fat diet. (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)

PRZYGODDA, FRANCIELE; LAUTHERBACH, NATALIA; BUZELLE, SAMYRA LOPES; GONCALVES, DAWIT ALBIEIRO; ASSIS, ANA PAULA; PAULA-GOMES, SILVIA; RISSATO GAROFALO, MARIA ANTONIETA; HECK, LILIAN CARMO; MATSUO, FLAVIA SAYURI; MOTA, RYERSON FONSECA; et al. Sympathetic innervation suppresses the autophagic-lysosomal system in brown adipose tissue under basal and cold-stimulated conditions. Journal of Applied Physiology, v. 128, n. 4, p. 855-871, APR 2020. (12/24524-6, 18/10089-2, 16/00508-2, 15/26088-7, 14/11092-6, 13/17111-0, 12/18861-0)

MOTA, RYERSON FONSECA; DE ARAUJO, PAULO HENRIQUE CAVALCANTI; CEZINE, MARIA EDUARDA RAMOS; MATSUO, FLAVIA SAYURI; METZNER, RODRIGO JAIR MORANDI; DE BIAGI JUNIOR, CARLOS ALBERTO OLIVEIRA; PERONNI, KAMILA CHAGAS; HAYASHI, HIROKI; SHIMAMURA, MUNEHISA; NAKAGAMI, HIRONORI; et al. RANKL Impairs the TLR4 Pathway by Increasing TRAF6 and RANK Interaction in Macrophages. BIOMED RESEARCH INTERNATIONAL, v. 2022, p. 13-pg., 2022-04-12. (16/22009-8, 16/00508-2, 14/11092-6, 16/00651-0, 15/26088-7)