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The role of HDL in lipopolysaccharides and advanced glycation end products signaling in macrophages: impact on inflammation and lipid homeostasis.

Grant number: 22/11186-7
Support Opportunities:Scholarships in Brazil - Master
Effective date (Start): April 01, 2023
Effective date (End): August 31, 2024
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Marisa Passarelli
Grantee:Danielle Ribeiro Santos
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil


The accumulation of cholesterol in macrophages in the arterial wall is accompanied by the infiltration of immune cells and the secretion of inflammatory cytokines. In these cells, the high expression of the receptor for advanced glycation products (AGER) and toll-like receptor 4 (TLR-4) triggers inflammatory pathways, after signaling by lipopolysaccharides (LPS) and/or advanced glycation products (AGE), which is linked to the lesion evolution, plaque rupture and acute cardiovascular events. Advanced glycated albumin (AGE-albumin) persistently sensitizes macrophages to the LPS-induced inflammation (priming), with increased secretion of cytokines. High-density lipoproteins (HDL) remove excess cholesterol and inhibit the inflammatory response in macrophages, contributing to the prevention of the genesis and evolution of atherosclerosis. Our hypothesis is that HDL is able to modulate tolerance or sensitization to LPS and AGE and the inflammatory response and lipid homeostasis in macrophages. The hypothesis that changes in HDL proteomics in sepsis is linked to changes in the functionality of this lipoprotein will also be evaluated. The objective of the present investigation is to evaluate the influence of HDL on tolerance or inflammatory sensitization to LPS and AGE and the impact on cellular lipid homeostasis and inflammation. Bone marrow-derived macrophages (BMDM) exposed or not to HDL will be incubated with LPS (24h), treated with control albumin or AGE (24h) and, after a new insult with LPS (24h), cytokine secretion will be determined by ELISA. The conditioned medium from these incubations will be used for the treatment of naive macrophages to determine the efflux of 14C-cholesterol. Similar experiments will be carried out with peritoneal macrophages obtained from mice treated with repetitive low doses of LPS. The expression of genes involved in the AGE-AGER-TLR-4 axis will be determined by RT-qPCR. The results will be important for understanding the role of HDL in the pathophysiology of inflammation in atherogenesis induced by the LPS/AGE axis, contributing to the establishment of therapies for the management of patients in acute cardiovascular events.

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