Metabolic rewiring of dendritic cells during the efferocytosis of apoptotic cells

Author(s)

Letícia de Aquino Penteado

• Document type: Doctoral Thesis
• Press: Ribeirão Preto.
• Institution: Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC)
• Defense date: 2023-09-04

Examining board members

Alexandra Ivo de Medeiros; José Carlos Farias Alves Filho; Larissa Dias da Cunha; Marco Aurelio Ramirez Vinolo

• Advisor: Alexandra Ivo de Medeiros; Pedro Manoel Mendes de Moraes Vieira

Abstract

Cellular activation integrates metabolic pathways to sustain cell function. The clearance of apoptotic cells (ACs), termed efferocytosis, activates glycolysis or β-oxidation for tissue repair. Toll-like receptor (TLR) stimulation activates glycolysis, fatty acid synthesis (FAS) and an inflammatory cell phenotype. Efferocytosis of Escherichia coliinfected ACs by dendritic cells (DCs) results in immunogenic DCs. However, little is known about the modulation of DC metabolic pathways in the presence of components derived from AC degradation and bacterial recognition. This study hypothesized that the phagocytosis of ACs would increase β-oxidation and oxidative phosphorylation, resulting in tolerogenic DCs and the efferocytosis of ACs infected with Staphylococcus aureus (iACs) would favor the activation of TLR, glycolysis and FAS, while the high lipid content from AC would allow activation of the β-oxidation pathway. The synergism of these pathways would contribute to DC function. Our results showed that efferocytosis of AC promoted an increase in the glycolytic pathway without altering DC phenotype. On the other hand, iAC efferocytosis promoted rapid cell activation with increased expression of MHC-II and CD86 molecules and production of inflammatory mediators and IL-10. This activation was followed by reduced mitochondrial respiration and increased production of mitochondrial reactive oxygen species (ROS) and dysfunctional mitochondria. Efferocytosis of iAC also enhanced glycolysis by activating the transcription factor Hif-1α. The inhibition of metabolic pathways demonstrated that glycolysis and FAS are important to produce IL-6, IL-1β, nitrite and IL-10 in this context. In diabetic mice, Langerhans cells become dysfunctional and unable to recruit Th17 cell response to resolve the cutaneous S. aureus infection. The transcriptome of the CD11c+ population isolated from the skin of infected diabetic mice showed downregulation of Hif1a, glycolysis, and the production of inflammatory cytokines genes. These data shed light on the contribution of these metabolic pathways in the activation of DCs and suggest possible therapeutic targets for the formulation of topical skin treatments that benefit diabetic individuals susceptible to skin infections. (AU)

• FAPESP's process: 18/19638-9 - Metabolic reprogrammation of dendritic cells after efferocytosis of apoptotic cells
• Grantee: Letícia de Aquino Penteado
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)