STING activation and regulation of macrophage polarization in LAP-deficient macrophages during efferocytosis

• Grant number: 19/21465-8
• Support Opportunities: Scholarships in Brazil - Master
• Start date: January 01, 2020
• End date: November 30, 2021
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Larissa Dias da Cunha
• Grantee: Daniel Leonardo Alzamora Terrel
• 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 critical for stress-related cellular homeostasis and therefore considered a promising target for drug development for various pathologies. However, the involvement of autophagic machinery in different cellular processes adds complexity to this goal. LC3-associated phagocytosis (LAP) is one of such processes, where the recruitment of components of the autophagic machinery directly to the phagosome regulates phagolysosomal maturation and subsequent signaling. Defects in LAP alter the degradation of phagocytosed dead cells, inducing the production of proinflammatory cytokines and chemokines (IL-1², IL-6, CCL2, CXCL10, among others), and reducing the levels of anti-inflammatory cytokines, such as IL-10. The immunosuppressive function of LAP in response to dead cells protects against the development of autoimmunity. This anti-inflammatory function of LAP is also evident in solid tumors, where phagocytosis of dead tumor cells by microenvironment macrophages promotes immunosuppression and sustains tumor growth. These evidences suggest that LAP can integrate efferocytosis and microenvironment signals in the regulation of macrophage gene expression and functional polarization towards an anti-inflammatory and tissue protection and repair profile, and may play a fundamental role in several inflammatory pathologies. In this context, this research project proposes to investigate how LAP of dead cell regulates macrophage polarization. Specifically, we will determine whether activation of STING, a cytosolic DNA sensor, regulates polarization in LAP-deficient macrophages. The role of STING will also be evaluated in the induction of autoimmunity in mice caused by defects in LAP machinery. (AU)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

TERREL, Daniel Leonardo Alzamora. Investigation of the role of STING in the loss of anti-inflammatory function in LAP-deficient macrophages in the context of efferocytosis. 2022. Master's Dissertation - Universidade de São Paulo (USP). Faculdade de Medicina de Ribeirão Preto (PCARP/BC) Ribeirão Preto.