Investigation of role of non canonical autophagy in metabolism regulation and macrophage functional polarization

• Grant number: 19/26311-9
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): October 01, 2020
• Status: Discontinued
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Larissa Dias da Cunha
• Grantee: Douglas dos Santos
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 18/25559-4 - Molecular mechanisms of LC3-associated phagocytosis and its role in macrophage function, AP.JP
• Associated scholarship(s): 24/04988-5 - Dissecting the regulation of macrophage metabolic wiring in response to efferocytosis, BE.EP.DD

Abstract

Clearance of dying cells is a pivotal function of the immune system. During the phagocytosis of apoptotic cells (efferocytosis), some components of the autophagy machinery can be directly recruited to the phagosome membrane, leading LC3 lipidation and mediating phagolysosomal maturation. This process is known as LC3-Associated Phagocytosis (LAP). We have recently established that LAP regulates the immune response to engulfed apoptotic cells. LAP-deficient macrophages fail to degrade engulfed cellular corpses, causing the expression of signature genes, cytokines and chemokines typical of reprogramming into inflammatory functional polarization. We have recently determined that this inflammatory polarization in LAP deficient macrophages is also characterized by an increase in the expression of components of the glycolytic pathway in response to dead cells. Conversely, reduced glucose availability suppressed production of inflammatory IL-6 in LAP-deficient macrophages during efferocytosis. Moreover, LAP deficiency increased the expression and the stability of HIF-1± in macrophages upon stimulation with dead cells, suggesting a possible participation of this transcription factor in metabolic reprogramming. Herein, we propose to investigate the mechanisms through which LAP controls macrophage functional polarization during efferocytosis, specifically inquiring the role of metabolism regulation in this process. (AU)