Characterization of the molecular mechanisms of LC3-associated phagocytosis and its role in disease pathogenesis

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Phagocytes of the innate immune system act as surveyors of their surroundings environment, patrolling the body for unwanted, unneeded, and unexpected components and eliminating them efficiently. While clearance of invading pathogens is a common and necessary function of phagocytes, the sensing, recognition, and removal of cellular corpses, a process termed efferocytosis, is also a critical role that phagocytes play during times of development, cellular homeostasis, and stress. Considering the average 50 billion adult human cells that undergo apoptosis daily and the rarity of observing an uncleared apoptotic cells under normal physiological conditions, one must truly appreciate the magnitude of the job facing phagocytes. Moreover, as this is a reoccurring and normal event in the lifespan of an organism, this process of efferocytosis must occur in a immunologically silent manner, so as to not inappropriately alert the immune system. Therefore, the response of a phagocyte must be tailored to both the cargo and the preferred outcome. The effective clearance of extracellular components (be it pathogens or dying cells) requires that phagocytes first recognize and engulf them using surface receptors, followed by processing of the cargo and orchestration of the appropriate local and systemic immune responses. The clearance of dead cells, however, is designed to be a tolerated mechanism, as cellular death is a normal, genetically programmed process designed to sculpt, control, and aid the body in its development and survival. The tightly orchestrated process of efferocytosis can be broadly organized in 4 steps: 1) the recruitment of phagocytes by find-me signals generated by dying cells, 2) the recognition and engagement of eat-me signals by receptors or bridging molecules from phagocytes, 3) the engulfment of the cellular corpse by phagocytes, and 4) the processing, degradation, and immune response to the engulfed corpse. While much work has been accomplished to characterize the molecules responsible for attracting the phagocyte and facilitating the physical engulfment, the mechanisms by which a phagocyte handles the ingested corpse in terms of its processing, degradation, and subsequent influence on the pursuant immune response is an area of growing interest. Recent studies have identified a unique process that is critical for the clearance of both pathogens and dying cells, as well as directing the subsequent immune response to each engulfed cargo. LC3-associated phagocytosis (or LAP) is a recently discovered pathway wherein a specific signaling event is sensed during phagocytosis and recruits some, but not all, members of the autophagy machinery to the phagosome. It is the activity of these autophagic players that facilitates the rapid destruction or processing of the cargo via fusion with the lysosomal pathway. Engagement of multiple types of receptors, including TLR1/2, TLR2/6, TLR4, FcR, and TIM4 has been shown to trigger LAP to form the single-membraned, cargo-containing phagosome, termed the LAPosome. LAP is a process that marries the evolutionarily conserved pathways of phagocytosis and autophagy and allows us to reimagine the impact of the autophagy machinery on innate host defense mechanisms. This paradigm-shifting realization expands the autophagy machinerys implications beyond intracellular housekeeping to host defense against extracellular threats and sheds new light on inflammation and autoimmunity.