Macrophages and neutrophils constitutively express a number of cell-surface receptors that stimulate the phagocytosis and intracellular killing of microbes bound to them, although some also signal through other pathways to trigger responses such as cytokine production. These phagocytic receptors include several members of the C-type lectin-like family (see Fig. 3.2). For example, Dectin-1 is strongly expressed by macrophages and neutrophils and recognizes β-1,3-linked glucans (polymers of glucose), which are common components of fungal cell walls in particular. Dendritic cells also express Dectin-1, as well as several other C-type lectin-like phagocytic receptors, which will be discussed in relation to pathogen uptake for antigen processing and presentation in Chapter 9. Another C-type lectin, the mannose receptor (MR) expressed by macrophages and dendritic cells, recognizes various mannosylated ligands, including some present on fungi, bacteria, and viruses; it was once suspected to have an important role in resistance to microbes. However, experiments with mice that lack this receptor do not support this idea. The macrophage mannose receptor is now thought to function mainly as a clearance receptor for host glycoproteins such as β-glucuronidase and lysosomal hydrolases, which have mannose-containing carbohydrate side chains and whose extracellular concentrations are raised during inflammation.
A second set of phagocytic receptors on macrophages, called scavenger receptors, recognize various anionic polymers and acetylated low-density lipoproteins. These receptors are structurally heterogeneous, consisting of at least six different molecular families. Class A scavenger receptors are membrane proteins composed of trimers of collagen domains (see Fig. 3.2).
Fig. 3.2 Macrophages express receptors that enable them to take up microbes by phagocytosis. First panel: macrophages residing in tissues throughout the body are among the first cells to encounter and respond to pathogens. They carry cell-surface receptors that bind to various molecules on microbes, in particular carbohydrates and lipids, and induce phagocytosis of the bound material. Second panel: Dectin-1 is a member of the C-type lectin-like family built around a single C-type lectin-like domain (CTLD). Lectins in general are based on a carbohydrate-recognition domain (CRD). The macrophage mannose receptor contains many CTLDs, with a fibronectin-like domain and a cysteine-rich region at its amino terminus. Class A scavenger receptors such as MARCO are built from collagen-like domains and form trimers. The receptor protein CD36 is a class B scavenger receptor that recognizes and internalizes lipids. Various complement receptors bind and internalize complement-coated bacteria. Third panel: phagocytosis of receptor-bound material is taken into intracellular phagosomes, which fuse with lysosomes to form an acidified phagolysosome in which the ingested material is broken down by lysosomal hydrolases.
Pattern recognition by cells of the innate immune system.
They include SR-A I, SR-A II, and MARCO (macrophage receptor with a collagenous structure), which all bind various bacterial cell-wall components and help to internalize bacteria, although the basis of their specificity is poorly understood. Class B scavenger receptors bind high-density lipoproteins, and they internalize lipids. One of these receptors is CD36, which binds many ligands, including long-chain fatty acids.
A third set of receptors of crucial importance in macrophage and neutrophil phagocytosis is the complement receptors and Fc receptors introduced in Chapters 1 and 2. These receptors bind to complement-coated microbes or to antibodies that have bound to the surface of microbes and facilitate the phagocytosis of a wide range of microorganisms.