It's a cell-eat-cell world: autophagy and phagocytosis

Abstract

The process of cellular eating, or the phagocytic swallowing of one cell by another, is an ancient manifestation of the struggle for life itself. Following the endosymbiotic origin of eukaryotic cells, increased cellular and then multicellular complexity was accompanied by the emergence of autophagic mechanisms for self-digestion. Heterophagy and autophagy function not only to protect the nutritive status of cells, but also as defensive responses against microbial pathogens externally or the ill effects of damaged proteins and organelles within. Because of the key roles played by phagocytosis and autophagy in a wide range of acute and chronic human diseases, pathologists have played similarly key roles in elucidating basic regulatory phases for both processes. Studies in diverse organ systems (including the brain, liver, kidney, lung, and muscle) have defined key roles for these lysosomal pathways in infection control, cell death, inflammation, cancer, neurodegeneration, and mitochondrial homeostasis. The literature reviewed here exemplifies the role of pathology in defining leading-edge questions for continued molecular and pathophysiological investigations into all forms of cellular digestion.

Figure 1

Normal phagocytosis of bacteria, demonstrated with immunofluorescence. A wild-type, EC-SOD–expressing, peritoneal macrophage (red) (Invitrogen CellTracker CMRA; Life Technologies, Carlsbad, CA) exposed to EGFP-expressing E. coli (green) rapidly internalizes several bacteria.

Figure 2

Major steps in phagocytosis and autophagy. The proper induction (A and B), cargo targeting (C), maturation (D and E), and completion of lysosomal clearance (F) are all important for both phagocytosis and autophagy. For phagocytosis, the recognition of danger signals from dead cells or microbial pathogens stimulates phagocyte migration. A number of different receptors are involved in capturing and internalizing bacterial, apoptotic, or particulate cargoes through a process enhanced by Atg proteins and dependent on a proper local redox environment maintained by EC-SOD. Once the phagocytic cargo is inside the phagosome, concentrated production of ROS or degradative enzymes are stimulated, depending on the ingested contents. Similarly, either general or localized insults within cells serve to trigger the membrane deposition of Atg 5—Atg 12 and of LC3 (through Beclin 1–dependent or independent mechanisms), which are essential for the extension of autophagic membranes. Whereas nonselective sequestration of cytoplasm is induced by starvation, damaged and potentially harmful cargoes need to be appropriately targeted to LC3-bound membranes. Autophagy is also induced by phagosome-derived signals to sequester pathogens that escape or damage the phagosome membrane. In turn, induction of the autophagic pathway serves to further promote phagosome–lysosomal fusion. Thus, these two complementary systems cooperate in removing exogenous and endogenous danger signals to limit proinflammatory, carcinogenic, and prodeath stimuli. For both phagocytic and autophagic pathways, inefficient lysosomal fusion or digestion can contribute to many classes of disease (red-shaded boxes). Accumulation of undigested lysosomal cargo is seen in aging and in chronic granulomatous disease (CGD), neurodegenerative diseases, and many other diseases or disorders. Inefficient utilization of digested products for energy production or in the regeneration of mitochondria and other essential cellular structures may also contribute to cell death and neurodegeneration.