Monocyte-derived macrophages are the second important type of effector cell (after neutrophils) for the innate immune response that follows trauma or acute infection. The various molecules involved in monocyte adhesion and transmigration from blood into tissues are probably similar to those for neutrophils, although they have not been studied as thoroughly. The functional activation of macrophages, however, is more complex than that of neutrophils. Macrophages exist in different levels or stages of metabolic and functional activity, each representing different “programs” of gene activation and synthesis of macrophage-derived cytokines and mediators. The categories of macrophages include
Resting and scavenging macrophages
Phagocytosis removes host cell debris in the process called scavenging. Resting macrophages are the classic scavenging cell, capable of phagocytosis and uptake of the following:
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dead cell membranes
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chemically modified extracellular protein (ie, acetylated or oxidized lipoproteins)
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sugar ligands, through mannose receptors
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naked nucleic acids
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bacterial pathogens
Resting monocytes express at least 3 types of scavenging receptors but synthesize very low levels of proinflammatory cytokines. Scavenging can occur in the absence of inflammation. See Clinical Example 1-4.
Primed macrophages
Resting macrophages become primed by exposure to certain cytokines. Upon priming, these cells become positive for MHC class II antigen and capable of functioning as APCs to T lymphocytes (see Chapter 2). Priming involves
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activation of specialized lysosomal enzymes, such as cathepsins D and E, for degrading proteins into peptide fragments
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upregulation of certain specific genes (ie, MHC class II), and costimulatory molecules (ie, B7.1)
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increased cycling of proteins between endosomes and the surface membrane.
Primed macrophages thus resemble dendritic cells. They can exit tissue sites by afferent lymphatic vessels to reenter the lymph node.
Activated and stimulated macrophages
Activated macrophages are classically defined as macrophages producing the full spectrum of inflammatory and cytotoxic cytokines; thus, they mediate and amplify acute inflammation, tumor killing, and major antibacterial activity. Epithelioid cells and giant cells represent different terminal differentiations of the activated macrophage.
Many different innate stimuli can activate macrophages, including
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cytokines derived from T lymphocytes and other cell types
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chemokines
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bacterial cell walls or toxins from gram-positive or acid-fast organisms
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complement activated through the alternative pathway
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foreign bodies composed of potentially toxic substances, such as talc or beryllium
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exposure to certain surfaces, such as some plastics
Activation of macrophages is also termed polarization. Some research classifies activated and stimulated macrophages as M1 or M2, based on the observation that certain stimuli produce distinct patterns of gene or protein expression under experimental conditions. The activation state seems to be somewhat reversible, suggesting that macrophages may switch between subsets (plasticity), depending on environmental signals. In fact, macrophage research suggests there are at least 9 distinct classes of macrophage activation. Consequently, although the M1/M2 model might be oversimplified, it does provide a framework for conceptualizing different levels of macrophage activation in terms of acute inflammation (Fig 1-2).
M1–classically activated macrophage characteristics include
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high production of proinflammatory cytokines and reactive nitrogen and oxygen intermediates
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promotion of T helper-1 (Th1) response
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strong microbicidal and tumoricidal activity
M2–alternatively activated macrophage characteristics include
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parasite containment
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promotion of tissue remodeling
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promotion of tumor progression
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immunoregulatory functions
Activated macrophages synthesize numerous mediators to amplify inflammation such as
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inflammatory or cytotoxic cytokines, such as IL-1, IL-6, and TNF-α
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reactive oxygen or nitrogen intermediates
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lipid mediators
As noted, macrophages that are partially activated to produce some inflammatory cytokines are termed stimulated or reparative macrophages (M2). Such partially activated macrophages contribute to fibrosis and wound healing through the synthesis of mitogens such as platelet-derived growth factors (PDGFs), metalloproteinases, and other matrix degradation factors as well as to angiogenesis through synthesis of angiogenic factors such as vascular endothelial growth factor (VEGF).
Excerpted from BCSC 2020-2021 series: Section 9 - Uveitis and Ocular Inflammation. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.