Chapter 2 : Macrophages: Microbial Recognition and Response

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Macrophages are derived from circulating monocytes and are found in all tissues throughout the body, especially the lung, spleen, liver, and bone marrow. The macrophage scavenger receptors were discovered by Brown and Goldstein and functionally described for their ability to bind modified low-density lipoproteins (LDLs), such as acetylated LDL (AcLDL) and oxidized LDL (OxLDL), but not native LDL molecules. This chapter focuses on scavenger receptors found on macrophages. Macrophage receptor with a collagenous structure (MARCO) is constitutively expressed by subpopulations of macrophages, in particular, those of the spleen marginal zone, medullary lymph nodes, and resident peritoneal macrophages. The C-type lectin receptors recognize carbohydrates on cell surfaces, circulating proteins, and pathogens. Macrophages have numerous receptors that are not involved in phagocytosis/endocytosis, but play a role in sensing microbial products and inducing signal transduction. The surfactant proteins bind to macrophages, altering their function by, for example, upregulating the expression of the mannose receptor and SR-A, thereby improving pathogen phagocytosis. The most important opsonins are circulating complement proteins and immunoglobulins, such as immunoglobulin G (IgG). Many cytokine receptors interact with the cytoplasmic kinases of the Janus kinase (JAK) family, which initiate a response through the signal transducer and activator of transcription (STAT) molecules. Macrophages produce a wide range of cytokines, which include interleukin molecules (IL), tumor necrosis factors (TNF), and chemokines (CC and CXC). Receptor ligation mediates many processes including phagocytosis, production of cytokines and chemokines, and ultimately activation of the humoral immune response to invading pathogens.

Citation: Plüddemann A, Gordon S. 2009. Macrophages: Microbial Recognition and Response, p 27-50. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch2

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Nonopsonic macrophage receptors. The scavenger receptors are grouped together as a result of their ability to bind modified low-density lipoprotein; however, they are structurally diverse. Class A scavenger receptors are structurally closely related. Scavenger receptor A (SR-A) is a trimeric type II transmembrane glycoprotein with distinct cytoplasmic, transmembrane, spacer, α-helical coiled-coil, collagenous, and C-terminal cysteine-rich domains. Macrophage receptor with a collagenous structure (MARCO) lacks the coiled-coil domain and exhibits a longer collagenous domain. The class B scavenger receptors CD36 and SR-BI consist of a large extracellular loop tethered to the membrane by two short transmembrane domains adjacent to the short N and C termini. The C-type lectin receptors all contain one or multiple C-type lectin domain(s). The mannose receptor (MR) is a type I transmembrane receptor with multiple C-type lectin domains (CTLDs), a fibronectin type II domain, and a cysteine-rich domain. DC-SIGN is a tetrameric type II transmembrane receptor where each subunit contains one CTLD. Dectin-1 contains one CTLD and has an immunotyrosine activation motif (ITAM) in the cytoplasmic region. See the text for references.

Citation: Plüddemann A, Gordon S. 2009. Macrophages: Microbial Recognition and Response, p 27-50. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch2
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Macrophages have many receptors that mediate their diverse functions. The receptors are located on the surface as well as in vacuolar compartments and the cytosol, thereby mediating recognition of extracellular and intracellular pathogens. The opsonic receptors include complement receptors (integrins) and Fc receptors (Ig superfamily) (discussed further elsewhere in this volume). They function in phagocytosis and endocytosis of complement- or antibody-opsonized particles, respectively ( ). Fc receptors have either an inhibitory (contain an immunoreceptor tyrosine-based inhibition motif [ITIM]) or activatory (contain an immunoreceptor tyrosine-based activation motif [ITAM]) effect on NF-κB induction ( ). NF-κB is a family of nuclear transcription factors that regulate production of proinflammatory mediators. Another group of phagocytic/endocytic surface receptors are the non-Toll-like receptors (NTLRs), which include the family of scavenger receptors and the C-type lectins ( ). Nonopsonic surface receptors that do not mediate phagocytosis/endocytosis but are important sensors of bacteria, fungi, and viruses are the Toll-like receptors (TLRs) ( ). Scavenger receptors have been shown to collaborate with TLRs to induce NF-κB and may also directly mediate NF-κB induction upon interaction with ligand. Ligand recognition by lectins induces NF-κB, both directly and in collaboration with TLRs. TLRs can induce both NF-κB and IRFs via a signaling cascade mediated by the adaptor molecules MyD88 and TRIF. Some TLRs are located within vacuoles and play a role in recognition of intracellular pathogens. Cytosolic viruses and bacterial products are recognized by the NOD-like receptors (NLRs) and RIG-like helicases (RLHs) ( ). NLRs induce NF-κB either directly or in collaboration with TLRs. RLHs either induce NF-κB and IRF via mediators that are located on the outer membrane of the mitochondria or induce caspase-1-mediated apoptosis via the adaptor molecule ASC. In addition to NF-κB and IRF induction, there are a multitude of other signaling pathways within macrophages that have been omitted for clarity. Abbreviations: ASC, apoptosis-associated speck-like protein containing a caspase recruitment domain; MyD88, myeloid differentiation primary response gene ( ); NOD, nucleotide binding oligomerization domain; TRIF, TIR domain-containing adaptor-inducing interferon-β. (Drawing, A. Plüddemann.)

Citation: Plüddemann A, Gordon S. 2009. Macrophages: Microbial Recognition and Response, p 27-50. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch2
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Pathogens have developed several mechanisms to survive inside macrophages. resides and multiplies in a vacuole studded with ribosomes due to interaction with the rough endoplasmic reticulum (RER). The organism secretes effector molecules via its type IV secretion system into the cell that inhibit phagosome/lysosome fusion. The 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 phagosome acquires the early endosome marker Rab5 but excludes the late endosomal 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 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. undergoes a conversion from a unicellular form to a multicellular hyphal form, which allows this fungus to escape the macrophage. The phagosome develops into an acidic phagolysosome containing Rab7 where the parasite is able to survive and replicate. Viruses such as the herpes simplex virus are able to inhibit the activation of antiviral mechanisms, such as the activation of interferon regulatory function (IRF) proteins that induce interferon production upon viral infection. See the text for references. (Drawing, A. Plüddemann.)

Citation: Plüddemann A, Gordon S. 2009. Macrophages: Microbial Recognition and Response, p 27-50. In Russell D, Gordon S (ed), Phagocyte-Pathogen Interactions. ASM Press, Washington, DC. doi: 10.1128/9781555816650.ch2
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