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Regulation of M2 macrophage polarization in the process of efferocytosis by LC3-associated phagocytosis (LAP)

Grant number: 19/19877-6
Support type:Scholarships in Brazil - Scientific Initiation
Effective date (Start): October 01, 2019
Effective date (End): September 30, 2020
Field of knowledge:Biological Sciences - Immunology
Principal Investigator:Larissa Dias da Cunha
Grantee:Marlon Fortes Rocha
Home 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

Macrophages are plastic cells capable of reprogramming themselves in a broad range of functions according to the stimulus. The limits in this functional plasticity spectrum are known as inflammatory polarization profile (M1) and anti-inflammatory and tissue repair polarization profile (M2). Overall, the M2 polarization depends on IL-4 and IL-13, two pleiotropic Th2 type cytokines that signal through dimerization of IL-4Ra receptor. Despite that, little is known about how the temporal regulation of macrophage polarization occurs, as well as how this phenomenon is restricted to damaged tissue, thus avoiding deleterious effects of chronic immunosuppression. Recent data demonstrated that recognition and clearance of apoptotic cells act as the first signal to induce an anti-inflammatory and tissue repair genetic program associated with IL-4 and IL-13 stimuli. The integration between efferocytosis and IL-4Ra signaling regulates the extent of M2 function either in vitro or in vivo. The association of autophagy machinery with phagocytosis (LC3-associated phagocytosis, LAP) regulates the degradation of engulfed apoptotic cells, playing an essential role in gene expression regulation and cytokines production in response to efferocytosis. Remarkably, LAP regulates the expression of M2-associated genes in response to dead cells phagocytosis, supporting macrophage immunosuppressive role in the tumoral microenvironment. Therefore it is possible that, in specific contexts, LAP integrate efferocytosis and Th2 signaling to induce macrophage genetic programming into an anti-inflammatory and immunotolerant profile. We hypothesize that LAP regulates signaling through IL-4Ra receptor during M2 macrophage polarization in response to the phagocytosis of dead cells phagocytosis. We thus propose to test this hypothesis in the context of efferocytosis both in vitro and using a sterile inflammation in vivo model.