Snowy Owl
Retired in 2010, In Memoriam
Recognition of Microbes by Phagocytes
Anthony L DeFranco, Richard M Locksley and Miranda Robertson
from Immunity: The Immune Response to Infection
Chapter 3: Innate Immunity
© 1999-2006 New Science Press Ltd
Anthony L DeFranco, Richard M Locksley and Miranda Robertson
from Immunity: The Immune Response to Infection
Chapter 3: Innate Immunity
© 1999-2006 New Science Press Ltd
http://www.biomedcentral.com/nspprimers/phagocytes/full/
Phagocytosis is a major mechanism for destruction of microbes
Figure 3-7.1
Mechanisms of particle internalization by phagocytic cells
The function of the collectins and the complement opsonins that we have described in the preceding five sections is to tag microbes that have penetrated the epithelial barrier, as well as apoptotic cells and other tissue debris, for destruction by phagocytosis. Phagocytosis is the process by which a single cell engulfs a large particle, generally defined as 1 micron in diameter or larger, and is important both for immune defense and for tissue repair and homeostasis. Many types of cells are capable of phagocytosis, but neutrophils, macrophages and dendritic cells are particularly active in this process and are known as professional phagocytes. Neutrophils are circulating cells that are recruited into the tissues at sites of infection and are highly specialized for the internalization and destruction of microorganisms; macrophages and dendritic cells are sentinel cells resident in the tissues: macrophages play an important part in tissue maintenance as well as in immune defense; the main function of dendritic cells is to initiate adaptive immune responses, and we shall defer detailed discussion of these cells until Chapter 4.
Phagocytosis is a receptor-mediated process in which specific recognition of a particle by receptors on the phagocyte triggers actin polymerization, engulfment of the particle and fusion of a vesicle containing the internalized particle with specialized intracellular organelles, granules and lysosomes, containing destructive enzymes and microbicidal products (Figure 3-7.1a). A related process is macropinocytosis, in which phagocytic cells take up large amounts of fluid in their extracellular environment, apparently without receptor recognition but also through a process that is dependent upon actin polymerization (Figure 3-7.1b).
Phagocytes have receptors that allow them to recognize and internalize microorganisms
Figure 3-7.2
Table of phagocytic receptors
Figure 3-7.3
Different types of phagocytic receptors
Phagocytes, and particularly macrophages and dendritic cells, carry an array of receptors that recognize many microbial and other targets. Not all of these induce phagocytosis: the Toll-like receptors (TLRs), for example, which we describe in subsequent sections, are an important family of signaling molecules that activate the production of inflammatory and anti-viral cytokines and the maturation of dendritic cells but do not directly stimulate their internalization. Receptors that directly induce internalization of bound particles are known as phagocytic receptors and fall into two categories: those that can directly recognize microbes, and those that bind to opsonized particles after soluble molecules have tagged them (Figure 3-7.2). Receptors that directly recognize microbes include the mannose receptor of macrophages (Figure 3-7.3), which recognizes branched α-linked mannose oligosaccharide chains found on the surfaces of many bacteria, fungi, and protozoa but absent from mammalian cells, and dectin-1, a C-type lectin that recognizes β-glucan polysaccharides found in various microbial cell walls. Interestingly, the mannose receptor also binds to some viruses, including influenza virus and HIV, presumably reflecting aberrant glycosylation of viral proteins for unknown reasons. A group of structurally diverse phagocytic receptors collectively known as scavenger receptors, by contrast, can often recognize components of apoptotic cells, as well as components of pathogens. Two, both belonging to a structural family known as the scavenger receptor A (SRA) family, contribute in particular to defense against bacterial infection. The prototype of the SRA family, scavenger receptor AI, originally defined by the ability to bind oxidated lipoprotein components of atherosclerotic plaques, binds LPS, lipoteichoic acid and intact Gram-negative and Gram-positive bacteria. Mice lacking this molecule are more susceptible to infections with Gram-positive bacteria, including Staphylococcus aureus and the intracellular pathogen Listeria monocytogenes, which is also less readily killed by the mutant macrophages in vitro. A highly related receptor called MARCO is expressed on macrophages in the marginal zone of the spleen, which filters the blood, and also mediates binding of intact bacteria and may help remove them from the bloodstream.
Opsonin receptors, which recognize particles indirectly, fall into two categories: the complement receptors C1qRp, CR3 and CR4, which bind to particles opsonized by complement components; and the Fc receptors, which bind to particles opsonized by antibodies, the versatile opsonins of adaptive immunity.
Although both microbes and apoptotic debris are targeted for destruction by phagocytosis, the mechanism and strength of the phagocytic response can vary, and this may depend upon whether the phagocytic receptor itself is specific for microbial components, or the phagocytic stimulus coincides with signals from other receptors binding to microbial molecules. This can be illustrated by the case of CR3, which has two binding sites, one for iC3b and a distinct one for microbial β-glucan polysaccharides. Binding to these two sites has distinct functional consequences. Binding iC3b alone leads to a phagocytosis characterized by slow fusion to lysosomes and a relatively weak microbicidal response, whereas if both the iC3b and the β-glucan binding sites of CR3 are engaged the microbicidal response is much more robust. This is a general feature of phagocytosis mediated by iC3b tagging of particles: it is greatly enhanced by simultaneous recognition of other immune ligands, either by CR3 itself or by another phagocytic receptor, such as the mannose receptor, which specifically recognizes microbial components. Alternatively, other signals such as proinflammatory cytokines can boost the phagocytic response to iC3b-opsonized particles. The relative mildness of the phagocytic response to iC3b alone presumably reflects the fact that the alternative pathway of complement can tag inert particles such as pollen and apoptotic cells as well as infectious agents.
We shall see in the next section that Fc receptors, which bind opsonins almost always specifically targeted at microorganisms, provide especially rapid and destructive phagocytosis of particles.
Definitions
dectin-1: a phagocytic C-type lectin receptor recognizing microbial β-glucan polysaccharides.
iC3b: a large proteolytic fragment of complement component C3b that has lost enzymatic activity in the complement pathway but is recognized by complement receptors 2, 3, and 4 (CR2, CR3, CR4) and activates phagocytosis.
macropinocytosis: process whereby cells take up large amounts of extracellular fluid independently of receptor binding to ligands.
mannose receptor: phagocytic receptor of macrophages and dendritic cells that binds to branched α-linked oligo mannose-containing molecules through its C-type lectin domains. Also called CD206.
opsonized: bound by soluble recognition elements of the innate or adaptive immune system, such as antibody, iC3b, and collectins, that are recognized by phagocytic receptors.
phagocytic receptor: cell surface molecule of phagocytes that binds microbes, viruses or apoptotic cells, either directly or through opsonins, and induces phagocytosis.
phagocytosis: receptor-mediated internalization of cells or other particles larger than 1 micron in diameter.
scavenger receptor: any of a structurally diverse group of receptors defined by their ability to bind polyanionic ligands such as oxidized low density lipoprotein (LDL), as occurs in atherosclerotic plaques. Most scavenger receptors additionally bind either microbial ligands or apoptotic cells.
References
Ehlers MR: CR3: a general purpose adhesion-recognition receptor essential for innate immunity.
Microbes Infect 2000, 2:289-294. [PubMed Abstract] [Publisher Full Text] OpenURL
Linehan SA, et al.: Macrophage lectins in host disease.
Microbes Infect 2000, 2:279-288. [PubMed Abstract] [Publisher Full Text] OpenURL
Peiser L, Gordon S: The function of scavenger receptors expressed by macrophages and their role in the regulation of inflammation.
Microbes Infect 2001, 3:149-159. [PubMed Abstract] [Publisher Full Text] OpenURL
