Complement Receptors and Their Role in Leukocyte Recruitment and Phagocytosis

Abstract

The complement system is deeply embedded in our physiology and immunity. Complement activation generates a multitude of molecules that converge simultaneously on the opsonization of a target for phagocytosis and activation of the immune system via soluble anaphylatoxins. This response is used to control microorganisms and to remove dead cells, but also plays a major role in stimulating the adaptive immune response and the regeneration of injured tissues. Many of these effects inherently depend on complement receptors expressed on leukocytes and parenchymal cells, which, by recognizing complement-derived molecules, promote leukocyte recruitment, phagocytosis of microorganisms and clearance of immune complexes. Here, the plethora of information on the role of complement receptors will be reviewed, including an analysis of how this functionally and structurally diverse group of molecules acts jointly to exert the full extent of complement regulation of homeostasis.

Keywords: cell migration; complement; complement receptors; inflammation; leukocyte; phagocytosis.

Figure 1

Schematic representation of the human complement system, which possesses three main pathways: the classical, the lectin and the alternative pathway. Scissors indicate proteolytic cleavage. FB, Factor B; FD, Factor D; MAC, membrane attack complex; MASP, MBL-associated serum protease; MBL, mannose-binding lectin.

Figure 2

Complement receptors and their main ligands. Schematic representation of human complement receptors on the plasma membrane with their corresponding complement protein ligands. For CR1, CR2, CRIg, and CR3/4, the binding areas for each specific ligand are indicated. In addition, for CR1, the receptor domains are identified at the left side of the receptor. CCP, complement control protein repeats; LHR, long homologous repeats; MBL, mannose-binding lectin.

Figure 3

Complement receptors play a crucial role in leukocyte recruitment to the inflammatory site. [1] In response to an inflammatory trigger (infection/tissue damage), leukocytes first roll over the activated endothelium through weak selectin-glycoprotein interactions (for clarity only leukocyte selectins and endothelial glycoproteins are shown here). [2] This allows interaction of leukocyte GPCRs (including C5aR but also other chemoattractant receptors) with chemoattractant molecules, produced by tissue-resident cells in response to and forming a chemotactic gradient toward the inflammatory trigger. This results in inside-out activation of integrins, changing their global conformation from a bent non-activated conformation to an extended, activated conformation with higher affinity for the integrin ligands ICAM-1, ICAM-2 and VCAM-1, which belong to the immunoglobulin (Ig) superfamily adhesion molecules [3]. This leads to a tight adhesion and arrest of the leukocytes to the endothelium. After integrin-mediated crawling to an optimal emigration spot directed by the chemotactic gradient, a transmigratory cup is formed and leukocytes transmigrate [4] through the endothelial barrier and the basement membrane into the surrounding tissue, where their migration will be guided further to the inflammatory site directed by the chemoattractant gradient [5].

Figure 4

Complement-mediated phagocytosis in the clearance of microorganisms and immune complexes. (Left side) Resident liver macrophages (Kupffer cells/KCs) engulf pathogens, immune complexes and various other particles through interactions with complement receptors. Opsonized (red dots) immune complexes (ICs) are transported to the liver via CR1 on the plasma membrane of circulating red blood cells (RBCs). In the liver, ICs interact with CR1 and scavenger receptors (not shown) on KCs, leading to IC phagocytosis, where after RBCs return to the circulation. Opsonized and free pathogens are recognized by CRIg on KCs and are subsequently engulfed. (Right side) Phagocytes (e.g., neutrophils) are attracted to a site of infection and reach the extracellular matrix by transmigrating across the endothelium. Once there, CR1 on neutrophils will be involved in the attachment of C3-opsonized particles to the cell, after which interaction with CR3 mediates phagocytosis. As the plasma membrane surrounds the target, forming a phagosome, the activation of the nicotinamide adenine dinucleotide phosphate (NADPH) complex and degranulation of neutrophilic granules initiate target degradation.