Regulation of microglial induced inflammation by non-canonical autophagy

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Project Summary Recently, our laboratory identified a novel form of non-canonical autophagy where elements of the canonical autophagy machinery conjugate LC3 to phagosomal membranes. As such, this process has been deemed LC3-associated phagocytosis (LAP). Studies utilizing both cells and mice that are deficient in the LAP pathway have shown that LAP is a mediator of macrophage polarization and inflammatory response. In the central nervous system, microglial cells are the resident macrophage-like immune cells that are responsible for either promoting or quenching inflammation. Like other macrophages, microglial cells can be immunologically activated and polarized to either a pro-inflammatory M1-phenotype or an anti-inflammatory M2-phenotype. As professional phagocytes and by virtue of a plethora of differing surface receptors, they are able to selectively phagocytose target material including amyloid plaques that are a characteristic of most neurodegenerative diseases. In the context of Alzheimer’s diseases (AD), recent evidence has demonstrated that amyloid phagocytosis and activation of microglial cells promotes polarization towards the pro-inflammatory M1-state, leading to pro-inflammatory cytokine production and subsequent neuroinflammation. Herein, we provide preliminary evidence demonstrating that LAP promotes polarization of activated microglia to the anti- inflammatory M2-phenotype. Moreover, we provide convincing evidence that the LAP mechanism is engaged during phagocytosis of β-amyloid in microglial cells. We hypothesize that LAP is protective against neuroinflammation by promoting anti-inflammatory polarization of microglial cells in response to β-amyloid. Therefore, the experiments designed in the first aim of this proposal are directed at evaluating the molecular mechanisms controlling cell polarization in response to β-amyloid in the presence or absence of LAP. The second aim is designed to address the significance of microglial LAP to neuroinflammation in vivo. To achieve this aim we will be using an established murine model of AD that replicates human disease. By exploring this novel mechanism at both the molecular and physiological levels, we will develop a more comprehensive understanding of how neuroinflammation is established and maintained during neurodegeneration. More importantly, the studies proposed will provide new opportunities for manipulation and development of new treatment methodologies.