RANKL System on macrophages M1/M2 polarization

• Grant number: 16/00651-0
• Support Opportunities: Scholarships in Brazil - Master
• Effective date (Start): March 01, 2016
• Effective date (End): February 28, 2018
• Field of knowledge: Biological Sciences - Morphology - Cytology and Cell Biology
• Principal Investigator: Mariana Kiomy Osako
• Grantee: Paulo Henrique Cavalcanti de Araújo
• 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

RANKL system consists of a triad of proteins: the receptor activator of NFkB (RANK), its ligand RANKL and the decoy receptor osteoprotegerin (OPG). This unique system of two receptors and one ligand is described in T cell and dendritic cell communication, development of mammary glands and bone metabolism. OPG is a biomarker related to cardiovascular diseases events, high rate of mortality following cerebral ischemia, type 2 diabetes. However, there is no biological explanation for the rise of OPG, nor its contribution in those diseases is known so far. Recently, we described the role of the RANKL system in vascular calcification and anti-inflammatory responses in macrophages during cerebral ischemia in murine model. Macrophages are key players on the innate immune system that switch from pro and anti-inflammatory profile upon activation of the classical or the alternative via. Bacterial components are classical activators of M1 polarization, since they activate specially toll like receptor-4 (TLR4), that signal to nuclear translocation of the nuclear transcription factor kappa-B (NFkB); in contrast, cytokines derived from type 2 T helper, as IL4, induce M2 polarization and anti-inflammatory responses via MAPK-Egr1 axis, that culminates on peroxisome proliferator-activated receptor-gamma (PPAR³) and gene expression related to, for example, tissue repair. In our preliminary studies, RANKL inhibited the activation of TLR4 in sepsis model, and increased the expression of PPARg in human monocyte cell line. However, the molecular mechanism underpinning the role of RANKL on macrophage M2 polarization is still unknown. Based on the relevance and potential of RANKL contribution in anti-inflammatory responses, the purpose of this Master Project is to elucidate the molecular mechanism of RANK-RANKL system in M2 polarization by focusing on PPARg pathway.