Molecular mechanisms of LC3-associated phagocytosis and its role in macrophage function

• Grant number: 18/25559-4
• Support Opportunities: Research Grants - Young Investigators Grants
• Duration: May 01, 2019 - April 30, 2024
• Field of knowledge: Biological Sciences - Immunology
• Principal Investigator: Larissa Dias da Cunha
• Grantee: Larissa Dias da Cunha
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated grant(s): 20/12093-7 - Multi-user equipment approved with grant 2018/25559-4: high-resolution motorized epifluorescence microscope, AP.EMU; 20/05288-6 - The role of efferocytosis in tissue repair and hyperinflammation in SARS-CoV-2 infection, AP.R
• Associated scholarship(s): 22/14525-7 - Characterization of molecular pathways associated with the type I IFN response in LAP-deficient macrophages in the context of efferocytosis, BP.DR; 22/15571-2 - Study of the mechanisms of tolerance induction during infections, BP.PD; 21/09909-8 - Molecular mechanisms of LC3-associated phagocytosis and its role in macrophage function, BP.TT; + associated scholarships 21/04605-0 - Advanced training in laboratory and mouse colony management, BP.TT; 20/13120-8 - Characterization and evaluation of sCD163 potential as severity biomarker in SARS-CoV-2 infection, BP.MS; 19/26311-9 - Investigation of role of non canonical autophagy in metabolism regulation and macrophage functional polarization, BP.DD; 19/26040-5 - Identification and characterization of novel molecular determinants of LC3-associated phagocytosis (LAP) in macrophages, BP.PD; 19/21465-8 - STING activation and regulation of macrophage polarization in LAP-deficient macrophages during efferocytosis, BP.MS; 19/19877-6 - Regulation of M2 macrophage polarization in the process of efferocytosis by LC3-associated phagocytosis (LAP), BP.IC; 19/14247-4 - Molecular mechanisms of LC3-associated phagocytosis and its role in macrophage function, BP.TT; 19/10588-1 - Advanced training in laboratory and mouse colony management, BP.TT - associated scholarships

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, inducing a lupus-like autoimmune syndrome in aging mice. This anti-inflammatory function of LAP is also 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. (AU)