Diversity and Versatility of Phagocytosis: Roles in Innate Immunity, Tissue Remodeling, and Homeostasis

Abstract

Phagocytosis, a critical early event in the microbicidal response of neutrophils, is now appreciated to serve multiple functions in a variety of cell types. Professional phagocytes play a central role in innate immunity by eliminating pathogenic bacteria, fungi and malignant cells, and contribute to adaptive immunity by presenting antigens to lymphocytes. In addition, phagocytes play a part in tissue remodeling and maintain overall homeostasis by disposing of apoptotic cells, a task shared by non-professional phagocytes, often of epithelial origin. This functional versatility is supported by a vast array of receptors capable of recognizing a striking variety of foreign and endogenous ligands. Here we present an abbreviated overview of the different types of phagocytes, their varied modes of signaling and particle engulfment, and the multiple physiological roles of phagocytosis.

Keywords: macrophage; neutrophil; phagocyte; phagocytosis; phagosome.

Figure 1

Phagocytosis of apoptotic neutrophils by a macrophage during the resolution of inflammation. The engulfment can be mediated by PS and/or the opsonization of the apoptotic neutrophils by thrombospondin. The thrombospondin-coated apoptotic cells are tethered to the macrophage by CD36, and the vitronectin receptor signals the initiation of phagocytosis. PS is recognized by the PS-receptor on the macrophage.

Figure 2

Phagocytosis of synaptic components by microglia. The classical complement cascade is initiated by the accumulation of C1q, produced by the microglia, at degenerating synapses. The C1q molecules bind CR1 on the microglial surface to form the C1 complex resulting in the eventual cleavage of C3. The fragments of C3 then opsonize the synaptic surface for subsequent phagocytosis via CR3. What targets C3 fragments to the synaptic membrane is unknown, thus it is depicted here as an unidentified molecule that may be a protein or a phospholipid. Other components of the C1 complex and complement cascade are not shown because they have not been studied in the context of synaptic pruning.

Figure 3

Phagocytosis of bacteria by neutrophils. The phagocytosis of bacteria is often mediated by opsonisation of their surface with IgG and C3b molecules, which are recognized by Fcγ receptors (FcγRs) and complement receptors (CRs), respectively.

Figure 4

Tumor-associated macrophages. The interaction between a macrophage (blue) and a tumor cell (green) is illustrated. The inset shows the membrane proteins involved in tumor cell evasion and promotion. CD47 is a “don't eat me” signal expressed on the tumor cell, which is recognized by SIRPα on the macrophage. Tumor cells secrete M-CSF, which is recognized by the M-CSF receptor on the surface of macrophages, leading to the secretion of EGF by the latter; a positive feedback loop between the two cells is thus generated. Metastatic cells express VCAM that interacts with the integrin VLA-4, which activates cell survival pathways in the metastatic cell.

Figure 5

Classical antigen presentation by a dendritic cell. Dendritic cells engulf a target, such as bacteria, forming a phagosome. Controlled bacterial degradation in the phagosome generates peptides that are used for antigen presentation on MHC class II molecules. The MHC class II molecule is synthesized and processed by the ER and Golgi complex, being delivered to an exocytosis-competent vesicle where it encounters and is loaded with antigenic peptides to form the peptide-MHC class II complex.