Chapter 23 : Complement Receptors in Myeloid Cell Adhesion and Phagocytosis

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Complement is a system of blood plasma proteins that play critical roles in host defense through attracting leukocytes to sites of inflammation, mediating myeloid cell uptake and destruction of microbes, and guiding B- and T-cell activation ( ). Regardless of the activation mechanism, the complement cascade converges on generation of third component of complement (C3) convertases that cleave C3 to C3a and C3b. The N-terminus of the C3α subunit is the anaphylatoxin (ANA) domain that becomes C3a after cleavage. C3b consists of two subunits containing eight macroglobulin-like domains (MG1 to -8). The β subunit consists of MG1 to MG5 plus the N-terminal half of MG6. The α subunit starts with the C-terminal half of MG6; a C1r/C1s, Uegf, and bone morphogenetic protein-1 (CUB) domain and a thioester domain (TED) inserted between MG7 and MG8; followed by the “anchor” and C345C domain (the trapezoid in Fig. 1 ).

Citation: Dustin M. 2017. Complement Receptors in Myeloid Cell Adhesion and Phagocytosis, p 429-445. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0034-2016
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Figure 1

Receptors for products of C3 expressed on human macrophages. Human macrophages differentiated from CD14 monocytes with granulocyte-monocyte colony-stimulating factor express all the major complement receptors, including C3aR, C5aR, CR1, CR3, and VSIG4. The arrows with the receptor names indicate approximate binding-site location within the schematic of C3 breakdown products that are released in the production of C3a, C3b, and its covalently attached products iC3b and C3d. The upper part of the schematic is the macrophage surface and the lower part is a microbial surface bearing the complement components.

Citation: Dustin M. 2017. Complement Receptors in Myeloid Cell Adhesion and Phagocytosis, p 429-445. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0034-2016
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Figure 2

Schematic of the mouse and human complement receptor gene products. In the mouse, CR1 and CR2 proteins are derived from alternative splicing of the gene. Mouse CR1 and CR2 are not present on myeloid cells. In humans, the CR1 and CR2 proteins are products of different genes. Human CR1 is expressed on myeloid cells and functions in phagocytosis in addition to clearance of immune complexes bearding C3b and/or C4b. CR1 also acts as a cofactor for factor I in conversion of C3b to iC3b and, further, to C3d. Each ball is an SCR, and each group of seven repeats is referred to as an LHR.

Citation: Dustin M. 2017. Complement Receptors in Myeloid Cell Adhesion and Phagocytosis, p 429-445. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0034-2016
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Figure 3

Fitting integrins and complement receptors into a diffusion barrier model for the phagocytic synapse. Close contacts are inherent to immunological synapses. Fc receptors and T-cell receptors naturally fit into a 15-nm gap that generates a diffusion barrier for entry of the RO and RB splice variants of CD45 and thus tips the local kinase/phosphatase balance in favor of the kinases. Large receptors like CR3 and CR4 are too large to fit into the <15-nm space when fully extended. Active F-actin-mediated processes induced by phosphatidylinositol-3 kinase (PI-3K) signaling can work with integrins to expand close contacts in phagocytic immune synapses and increase the area from which CD45 is excluded. The relevant integrin conformations that mediate this close contact formation are not known, but may include alternative crouching conformations recently described by electron microscopy or tilted extended conformations generated by forces tangential to the membrane. CR1 function overlaps extensively with CR3/4, and thus it is possible that CR1 can also adopt conformations that facilitate close contact in an F-actin-dependent manner, despite its apparent large size. Further study is needed to understand whether CR1 also participates in close contact formation and how CR1’s structure is adapted to this task.

Citation: Dustin M. 2017. Complement Receptors in Myeloid Cell Adhesion and Phagocytosis, p 429-445. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0034-2016
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Table 1

Complement receptors involved in adhesion, migration, and phagocytosis

Citation: Dustin M. 2017. Complement Receptors in Myeloid Cell Adhesion and Phagocytosis, p 429-445. In Gordon S (ed), Myeloid Cells in Health and Disease. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.MCHD-0034-2016

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