Chapter 19 : Macrophage Classical Activation

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This chapter focuses on the critical steps of classical macrophage activation that have been emphasized by rare human diseases in which key components such as macrophages, are naturally deficient. In conjunction with other cells, macrophages will form granulomas. Numerous molecules are definitely or putatively involved in this process, and a few have been identified by natural mutations. The author reviews these through an arbitrary and artificial division of the proinflammatory response into premacrophage, intramacrophage, and post-macrophage phases. The activated TAK-1 activates the IκB kinase (IKK) complex; this complex is composed of two catalytic subunits, IKK αand IKK β, and the regulatory subunit IKKγ. Peripheral blood monocytes and primary macrophage cultures from patients with classical Wiskott-Aldrich syndrome (WAS) also demonstrate impaired FcγR-mediated phagocytosis due to defective phagocytic cup formation. Previous explanations for the selective infection susceptibility in chronic granulomatous disease (CGD) relied on microbial catalase as a critical virulence factor. The argument was that, whereas CGD phagocytes lacked superoxide and hydrogen peroxide production, hydrogen peroxide-producing microbes would complement the defect in the CGD cell unless they also produced catalase to degrade their own hydrogen peroxide. In summary, CGD neutrophils and macrophages are defective in O production. The phagosome gradually acquires molecules necessary for lysosomal fusion to produce the phagolysosome. Defects in lysosomal degradation typically result in intracellular accumulation of undegraded substrates, characterized by neurodegeneration without associated immunodeficiency. The classically activated macrophage is an IFN-γ -primed cell that recognizes, via specific cell surface receptors, microbes and their products.

Citation: Vinh D, Holland S. 2009. Macrophage Classical Activation, p 301-323. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch19
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TLRs are pattern-recognition receptors that distinguish among PAMPs. Structurally, TLRs contain extracellular leucine-rich repeats responsible for recognition of their respective PAMPs, a transmembrane domain that determines their cellular localization and an intracellular domain that mediates signaling pathways. Ligand binding induces TLR oligomerization or heterodimerization, responsible for PAMP specificity; subsequent recruitment of a particular network of adaptor proteins allows for specific intracellular signaling. Here, TLR4-mediated signaling is depicted (see text for details). Selected ligands for the 10 human TLRs are shown here as follows: TLR1, triacyl lipopeptides (LP); TLR2, peptidoglycan (PG); TLR3, double-stranded RNA (dsRNA); TLR4, lipopolysaccharide (LPS); TLR5, flagellin (Fl); TLR6, diacyl lipopeptides (DALP); TLR7, imiquimod (Im); TLR8, single-stranded RNA (ssRNA); TLR9, unmethylated CpG dinucleotides (CpG); TLR10, undefined.

Citation: Vinh D, Holland S. 2009. Macrophage Classical Activation, p 301-323. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch19
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Critical components for macrophage phagocytosis and phagosomal maturation to form the phagolysosome. Key molecules are listed (see text for details). Opsonization with IgG allows for FcγR-mediated internalization of pathogens or particles (ingestion). Subsequently, various kinases and secondary messenger molecules allow for reorganization of the macrophage cytoskeleton, specifically, actin assembly at the plasma membrane area engaged with the opsonized pathogen and the formation of cell membrane protrusions (phagocytic cup). Continuous growth of these protrusions allows for pseudopods to surround the pathogen, allowing for subsequent engulfment. The nascent phagosome, containing the pathogen, moves centripetally via myosins and other intracellular machinery. Maturation of the phagosome requires coordinated fusion with various vesicles, including the early endosome, the late endosome, and the lysosome, during which the protein content of both the phagosome membrane and the phagosome lumen are modified.

Citation: Vinh D, Holland S. 2009. Macrophage Classical Activation, p 301-323. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch19
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The macrophage respiratory burst. Early in the process following phagocytosis, the NADPH oxidase assembles on the phagosome. This multisubunit enzyme complex allows for the respiratory (or oxidative) burst, whereby ROS (i.e., superoxide anion [O ] and hydrogen peroxide [HO]) are generated within the phagosome. The ROS contribute to pathogen killing, primarily by activating pathways culminating in the expression of proinflammatory genes.

Citation: Vinh D, Holland S. 2009. Macrophage Classical Activation, p 301-323. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch19
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Cytokine networks critical for classical macrophage activation. On interaction with select intracellular pathogens, activated macrophages produce proinflammatory cytokines that act in a paracrine or autocrine manner to augment intracellular killing mechanisms.

Citation: Vinh D, Holland S. 2009. Macrophage Classical Activation, p 301-323. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch19
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