Fig. 3.7 Phagocytosis and intracellular destruction of microbes. (A) Phagocytosis of a particle (e.g., a bacterium) involves binding to receptors on the leukocyte membrane,engulfment,and fusion of the phagocytic vacuoles with lysosomes.This is followed by destruction of ingested particles within the phagolysosomes by lysosomal enzymes and by reactive oxygen and nitrogen species. (B) In activated phagocytes, cytoplasmic components of the phagocyte oxidase enzyme assemble in the membrane of the phagosome to form the active enzyme, which catalyzes the conversion of oxygen into superoxide ( O2 − ) and H2O2. Myeloperoxidase, present in the granules of neutrophils, converts H2O2 to hypochlorite. (C) Microbicidal reactive oxygen species (ROS) and nitric oxide (NO) kill ingested microbes. During phagocytosis, granule contents may be released into extracellular tissues (not shown). iNOS, Inducible NO synthase; MPO, myeloperoxidase; ROS, reactive oxygen species.
intracellular killing. Several other responses aid in the defensive functions of inflammation and may contribute to its injurious consequences.
Phagocytosis involves three sequential steps: (1) recognition and attachment of the particle to be ingested by the leukocyte; (2) engulfment, with subsequent formation of a phagocytic vacuole; and (3) killing or degradation of the ingested material (
Fig. 3.7 ). These steps are triggered by activation of phagocytes by microbes, necrotic debris, and various mediators.
Recognition by Phagocytic Receptors. Mannose receptors, scavenger receptors, and receptors for various opsonins bind and ingest microbes. The macrophage mannose receptor is a lectin that binds terminal mannose and fucose residues of glycoproteins and glycolipids. These sugars are typically part of molecules found on microbial cell walls, whereas mammalian glycoproteins and glycolipids contain terminal sialic acid or N-acetylgalactosamine. Therefore, the mannose receptor recognizes microbes and not host cells. Scavenger receptors bind and ingest low-density lipoprotein (LDL) particles as well as a variety of microbes. The efficiency of phagocytosis is greatly enhanced when microbes are opsonized (coated) by specific proteins (opsonins) for which the phagocytes express high-affinity receptors. The major opsonins are immunoglobulin (Ig)G antibodies, the C3b breakdown product of complement activation, and certain plasma lectins, notably mannose-binding lectin, all of which are recognized by specific receptors on leukocytes.
Engulfment. After a particle is bound to phagocyte receptors, extensions of the cytoplasm (pseudopods) flow around it, and the plasma membrane pinches off to form a cytosolic vesicle (phagosome) that encloses the particle. The phagosome then fuses with lysosomes, resulting in the discharge of lysosomal contents into the phagolysosome (
Fig. 3.7 ). During this process the phagocyte also may release some granule contents into the extracellular space, thereby damaging innocent bystander normal cells.
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Intracellular Destruction of Microbes and Debris
The killing of microbes and the destruction of ingested materials are accomplished by reactive oxygen species (ROS, also called reactive oxygen intermediates), reactive nitrogen species, mainly derived from nitric oxide (NO), and lysosomal enzymes (