Metabolic reprogrammation of dendritic cells after efferocytosis of apoptotic cells

• Grant number: 18/19638-9
• Support type: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): May 01, 2019
• Effective date (End): June 30, 2022
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal researcher: Alexandra Ivo de Medeiros
• Grantee: Letícia de Aquino Penteado
• Home Institution: Faculdade de Ciências Farmacêuticas (FCFAR). Universidade Estadual Paulista (UNESP). Campus de Araraquara. Araraquara , SP, Brazil

Abstract

The dynamic of immune cells to respond to foreign antigen while maintaining tolerance to self-antigens requires constant metabolic adaptation. Dendritic Cells (DC) play a crucial role in the recognition of pathogens as well as in the clearance of Apoptotic Cells (AC) during infection or injury. We have recently showed that the clearance of AC in the absence of an infection leads to tolerogenic DC, while efferocytosis of infected Apoptotic Cells (iAC) results in immunogenic DC that are capable to produce both anti and pro-inflammatory mediators. It has been reported that DC activation leads to a switch from mitochondrial metabolism to glycolysis to support the requirements of DC function. However, the outcome of signals derived from the AC and PAMPs inside the cell corpse on the metabolic profile of DC remains elusive. We hypothesized that phagocytosis of ACs by DCs leads to an increase in fatty-acid and mitochondrial oxidative metabolism. This results in IL-10, TGF-² e PGE2 synthesis by tolerogenic DCs. On the other hand, iAC efferocytosis activates both TLR and efferocytic receptors, which promotes mTOR/HIF-1±-dependent glycolytic reprogramming together with mitochondrial metabolism. Both signaling will contribute to the production of anti and pro-inflammatory mediators and non-canonical DC activation. This study aims to elucidate the metabolic reprogramming that leads to tolerogenic or immunogenic dendritic cell after efferocytosis of AC or iAC, respectively. (AU)