Regulation of macrophage M2 polarization in the process of LC3-associated phagocytosis

• Grant number: 23/08654-1
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: July 01, 2023
• End date: December 31, 2023
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Larissa Dias da Cunha
• Grantee: Wanderson Cawan Dourado Souza
• 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

Abstract

Autophagy is pivotal for cell homeostasis upon environmental stress and thus considered a promising therapeutic target for different pathologies. However, the role of autophagic components in diverse cell processes adds complexity to this goal. LC3-associates phagocytosis is one such processes, where the direct recruitment of components of autophagic machinery to the phagosome membrane regulates phagolysosomal maturation and downstream signaling cascade. LAP is fundamental for macrophage secretion of anti-inflammatory cytokines in response to the engulfment of dying cells (efferocytosis). Impairment of LAP, but not canonical autophagy, causes defects in the elimination of dying cells. This anti-inflammatory function of LAP is evident in solid tumors, where the phagocytosis of dying tumor cells by associated macrophages causes immunosuppression and promotes tumor growth. In the absence of LAP, tumor macrophages tune in to a pro-inflammatory gene expression program and trigger cytosolic STING-mediated type I interferon production, which causes T cell activation and restriction of tumor growth. These evidences suggest that LAP may integrate efferocytosis and environmental cues into anti-inflammatory and tissue repair functional polarization of macrophages, playing a role in diverse inflammatory pathologies as well as in the balance of resistance and tolerance to infectious diseases. In this context, this proposal aims to elucidate the role of LAP in macrophage polarization during efferocytosis and to reveal novel components of the molecular cascade of LAP.