A guide to chemokines and their receptors

Abstract

The chemokines (or chemotactic cytokines) are a large family of small, secreted proteins that signal through cell surface G protein-coupled heptahelical chemokine receptors. They are best known for their ability to stimulate the migration of cells, most notably white blood cells (leukocytes). Consequently, chemokines play a central role in the development and homeostasis of the immune system, and are involved in all protective or destructive immune and inflammatory responses. Classically viewed as inducers of directed chemotactic migration, it is now clear that chemokines can stimulate a variety of other types of directed and undirected migratory behavior, such as haptotaxis, chemokinesis, and haptokinesis, in addition to inducing cell arrest or adhesion. However, chemokine receptors on leukocytes can do more than just direct migration, and these molecules can also be expressed on, and regulate the biology of, many nonleukocytic cell types. Chemokines are profoundly affected by post-translational modification, by interaction with the extracellular matrix (ECM), and by binding to heptahelical 'atypical' chemokine receptors that regulate chemokine localization and abundance. This guide gives a broad overview of the chemokine and chemokine receptor families; summarizes the complex physical interactions that occur in the chemokine network; and, using specific examples, discusses general principles of chemokine function, focusing particularly on their ability to direct leukocyte migration.

Keywords: atypical chemokine receptor; cell migration; chemokine; chemokine receptor; glycosaminoglycan; immune surveillance; inflammation; leukocyte; oligomerization; protease.

Figure 1

Mammalian chemokine receptors and their known interactions with chemokines and other key secreted, cell surface, and pathogen‐encoded molecules. Chemokines of the four subclasses (CCL, CXCL, CX ₃ CL, and XCL) are arranged numerically in columns and represented as numbered squares that are color‐coded according to whether they are in humans and mice, humans only, or mice only (see Key). The chemokine–chemokine ‘interactome’ 40 is not depicted. Chemokines are linked by lines to receptors that they are known to bind: yellow boxes are atypical chemokine receptors (ACKRs) (previous names shown in parentheses); green boxes are conventional chemokine receptors (cCKRs); and light green boxes show reported human cCKR variants generated by alternative splicing at the N terminus (CCR9, CXCR3, CXCR4) or C terminus (CCR2) 69, 70, 71, 72, 73, 74. The color of the linking line (see Key) indicates whether the interaction likely exists in humans only, mice only, or in humans and mice. Hashed black lines ending with a filled circle link chemokines with receptors they can antagonize 119, 120, 121, 122, 123, 124, 125, 126. CXCL14 is reported to be a positive allosteric modulator of CXCR4 344. Chemokine receptors reported to form heterodimers are linked with a black line 93, 94, 95, 96, 97, 98, 99, 100, 101, 118. Nonchemokine proteins in light pink boxes are able to activate the cCKR they are joined to by a black line 89, 90, 91, 92, 102, 347. White boxes contain microbial proteins (red text) and other host extracellular/surface proteins (black text; nonchemokine, nonchemokine receptor) that have been reported to interact, in the absence of chemokine, with the cCKR or ACKR to which they are attached by a black line [32, 92, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 147, 148, 149, 150, 151, 152, 167, 233, 264, 345, 346, 347, 348]. Note that cCKRs and ACKRs other than those shown are known to be capable of binding HIV and/or gp120, but the role of these chemokine receptors during infection is uncertain. CCL18 receptor PITPMN3 and CCL5 receptor GPR75 are also shown 127, 348. FPRL1 interacts with a peptide released proteolytically from the N terminus of one form of CCL23 20. Gray boxes show drugs in clinical use: Maraviroc 143 and Plerixafor 237, antagonists of CCR5 and CXCR4, respectively; and Mogamulizumab, a humanized anti‐CCR4 antibody approved for treatment of relapsed or refractory CCR4+ adult T‐cell leukemia/lymphoma (CTCL) 349. Definitions: ADM, adrenomedullin; ADRA1A/B, α1A/B‐adrenoreceptors; C‐18, cyclophilin‐18 of Toxoplasma gondii; CB2, cannabinoid receptor 2; DBP, Duffy binding protein of malarial parasites P. vivax and P knowlesi; DOR, delta‐opioid receptor; GluR1, component of the AMPA‐type glutamate receptor; Glyco G, RSV G glycoprotein; gp120, the gp120 envelope protein of HIV; GPR75, G protein‐coupled receptor 75; HlgAB, Staphylococcus aureus γ‐Hemolysin AB; HMGB1, high mobility group box 1 protein; KOR, kappa‐opioid receptor; LukED, S. aureus leukotoxin ED; MIF, macrophage migration inhibitory factor; MOR, mu‐opioid receptor; PITPMN3, phosphatidylinositol transfer protein 3; PSMP, PC3‐secreted microprotein; TCR, T‐cell receptor; TSG‐6, TNF‐stimulated gene 6; β2AR, β2‐adrenergic receptor. Extended from previous reviews 64, 350.

Figure 2

Functions of chemokines and their receptors. Biological processes reported to be regulated by chemokines and their receptors are in light blue boxes arranged clockwise, in alphabetical order (starting bottom left), around the central ‘Chemokines & Receptors’ box. ‘Cell Movement’ is depicted as the dominant biological process regulated by chemokines and their receptors: chemokine‐mediated cell arrest/adhesion, and the different types of migratory behavior known to fall under chemokine control, are shown in light green boxes.

Figure 3

Expression of chemokine receptor genes in selected mouse leukocytes and stromal cells. The figure was generated using transcriptomic data from The Immunological Genome Project database (http://www.immgen.org) 351. The maximum expression value was identified for the cell types shown and is indicated in the row at the bottom of the Figure in arbitrary units. For each receptor, this value was set to 100%. Estimated background values (typically between 50 and 100) were determined by examining expression graphs for all cell types on the database. Expression in the cell types shown in the left hand column was then assigned a color according to the percentage of the maximum expression value (see Key on right). Note that not all cells in a cell population will necessarily express the receptor. BM, bone marrow; DC, dendritic cell.

Figure 4

Expression of chemokine genes in selected mouse tissues under steady‐state conditions. By examining graphs generated on The Immunological Genome Project website (http://www.immgen.org) 351 using their transcriptomic data, the expression of each chemokine, in each of the tissues shown (left hand column), was assigned to one of the seven color‐coded ‘Expression Level Categories’ indicated in the key in the center of the Figure. Expression in the central nervous system (CNS) was estimated by examining ImmGen data on numerous component parts of the CNS. Expression by lymphocytes was included to help indicate whether chemokine expression by secondary lymphoid organs could be attributed to expression by lymphocytes, the dominant cell type in these organs. It was estimated by examining ImmGen data on B cells, CD4+ T cells, and CD8+ T cells. It should be noted that the function of a chemokine in a tissue will depend of where it is expressed: for example, expression by blood vessel endothelial cells may enable leukocyte recruitment from the blood, while their presence elsewhere might help direct leukocytes to specific microanatomical niches, or encourage departure via lymphatic vessels.