LC3-Associated Phagocytosis and Inflammation

Abstract

LC3-associated phagocytosis (LAP) is a novel form of non-canonical autophagy where LC3 (microtubule-associated protein 1A/1B-light chain 3) is conjugated to phagosome membranes using a portion of the canonical autophagy machinery. The impact of LAP to immune regulation is best characterized in professional phagocytes, in particular macrophages, where LAP has instrumental roles in the clearance of extracellular particles including apoptotic cells and pathogens. Binding of dead cells via receptors present on the macrophage surface results in the translocation of the autophagy machinery to the phagosome and ultimately LC3 conjugation. These events promote a rapid form of phagocytosis that produces an “immunologically silent” clearance of the apoptotic cells. Consequences of LAP deficiency include a decreased capacity to clear dying cells and the establishment of a lupus-like autoimmune disease in mice. The ability of LAP to attenuate autoimmunity likely occurs through the dampening of pro-inflammatory signals upon engulfment of dying cells and prevention of autoantigen presentation to other immune cells. However, it remains unclear how LAP shapes both the activation and outcome of the immune response at the molecular level. Herein, we provide a detailed review of LAP and its known roles in the immune response and provide further speculation on the putative mechanisms by which LAP may regulate immune function, perhaps through the metabolic reprogramming and polarization of macrophages.

Oxidative Stress and Dysfunctional Intracellular Traffic Linked to an Unhealthy Diet Results in Impaired Cargo Transport in the Retinal Pigment Epithelium (RPE)

“…Our results indicate that a proportion of POS cargos had bypassed the conventional trafficking pathway, suggesting a compensatory mechanism as a consequence of lysosomal dysfunction. Recent findings have revealed a non‐canonical form of autophagy termed LC3‐associated phagocytosis (LAP) through which lipidated LC3 associates with phagosomes in an Atg5 and Beclin1‐dependent manner, but independently of the autophagy pre‐initiation Alk1/Atg13/Fip200 complex. The importance of this pathway was demonstrated in mice lacking Atg5 where phagosomes contained undigested POS were unable to penetrate into the RPE.…”

Autophagy-Independent Functions of the Autophagy Machinery

“…This process, however, occurs independently of ULK1, ATG13, and FIP200, which are all required for conventional autophagic responses (Kim et al, 2013). Thus, at least some of the phenotypes originating from the depletion of the aforementioned proteins may stem from defects in LAP, not autophagy, especially in the context of pathogen control and disposal of cell corpses (Heckmann et al, 2017). Interestingly, the orthologs of ATG9 and ATG16L1 also mediate autophagy-independent pro-phagocytic effects in Dictyostelium discoideum, a simple eukaryote that transitions from unicellular to multicellular life over the course of its vital cycle (Tung et al, 2010;Xiong et al, 2015).…”

Triggering MSR1 promotes JNK‐mediated inflammation in IL‐4‐activated macrophages

“…It has recently been acknowledged that the phagosome serves as a signalling platform and interacts with innate immune signalling (Stuart et al, 2007;Martinez et al, 2011Martinez et al, , 2015Kagan, 2012;Heckmann et al, 2017). However, whether phagosome-associated cell signalling is independent of its role in cargo degradation has not been well understood.…”