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1064 Part VIII: Monocytes and Macrophages Chapter 67: Structure, Receptors, and Functions of Monocytes and Macrophages 1065

Lysosomes

EEA1
Rab5

Rab5
Rab7

Myco- Rab7 Lamps
bacterium Listeria Legionella Francisella Influenza Leishmania Candida
Bacteria Virus Parasites Fungi

Figure 67–15. Selected pathogens evade distinct phagocytic mechanisms. Pathogens have developed several mechanisms to enter and survive
inside macrophages. Legionella pneumophila resides and multiplies in a vacuole studded with ribosomes as a result of interaction with the rough
endoplasmic reticulum. The organism secretes effector molecules via its type IV secretion system into the cell, which inhibit phagosome/lysosome
fusion. The Francisella tularensis phagosome acquires the early endosome markers EEA1 and Rab5 and then matures into a late endosome defined by
the presence of the markers Lamp1, Lamp2, and Rab7. The late endosome does not acidify and the phagosomal membrane is disrupted, releasing
the bacteria into the cytosol. The Mycobacterium tuberculosis phagosome acquires the early endosome marker Rab5 but excludes the late endoso-
mal Lamps and Rab7. This organism also produces molecules that block fusion with the lysosome and resides and replicates in this early endosome.
Acidification of the Listeria monocytogenes phagosome is essential for the perforation of the phagosomal membrane and escape of the bacteria into
the cytosol. Here they mobilize the actin polymerization machinery to move within the cell and then from cell to cell. Candida albicans undergoes
a conversion from a unicellular form to a multicellular hyphal form, which allows this fungus to escape the macrophage. The Leishmania mexicana
phagosome develops into an acidic phagolysosome containing Rab7 where the parasite is able to survive and replicate. Viruses such as the influenza
virus are able to inhibit the activation of antiviral mechanisms, such as the activation of IFN regulatory function proteins that induce IFN production
upon viral infection, and enter the nucleus. Cytomegalovirus (not shown) incapacitates a range of major histocompatibility complex-antigen present-
ing pathways. (Used with permission of S. Seif, GraphisMedica, 2014.)

GENE EXPRESSION, SYNTHESIS, constitutively expressed in vitro, but upregulated in granulomata in
vivo. The secretion pathway of lysozyme in monocytes and macro-
AND SECRETION phages has not been defined. The well-known pro- and antiinflam-
The development of microarray technology has had a dramatic matory cytokines are better characterized, both in terms of regulation
impact on the analysis of macrophage gene expression in response to and the secretion pathway. The response to IL-6 and TNF-α secre-
109
a wide range of stimuli, including microbial ligands, cytokines, and tion in model systems shows a more complex pathway than previously
immunomodulators. Macrophages are able to express a large number recognized. 127,128 In addition to these and other important growth and
of genes and are extremely versatile in their responses to environ- differentiation factors that regulate angiogenesis, for example, mac-
mental cues. It has been possible to discern signatures of particu- rophages are able to produce and secrete enzymes and proenzymes
lar agonists, for example, IFN-α and -β and IL-4, but many caveats for a range of activities, as well as their inhibitors, for example, pro-
remain in the interpretation of such data. Heterogeneity of cellular teinases and antiproteinases. Although the amounts of complement
origin, differentiation stage, and populations from diverse origins, as proteins produced, for example, are relatively small, they can be sig-
well as substantial species differences, make it difficult to compare nificantly concentrated in a local microenvironment. In addition,
results within and among experiments. Validation of more quantita- macrophages can produce a range of antimicrobial peptides and lytic
tive messenger RNA analysis of protein synthesis and modification is agents, but their most important killing mechanisms depend on oxy-
difficult, although proteomic analysis is gaining ground. The study of gen and nitrogen metabolites, 109,114 which are illustrated in Figs.
129
macrophage chromatin organization in relation to gene expression is 67–19 and 67–20. Regulation of the nicotinamide adenine dinucle-
in its infancy. otide phosphate oxidase and of inducible nitric oxide synthase has
There is extensive crosstalk between the secretory and endo- been studied extensively in mice and humans through biochemical
cytic pathways. Table 67–6 is a selected list of secretory products. and genetic approaches. Apart from their antimicrobial activity, nitro-
126
This includes lysozyme, a major myelomonocytic product that is gen metabolites contribute to signaling pathways. IFN-α and -β play
130

Kaushansky_chapter 67_p1043-1074.indd 1064 9/21/15 10:43 AM