Chemokines and Chemokine Receptors

Abstract

Chemokines (CKs) are a family of small proteins secreted by a great variety of cell types. Their name (derived from chemoattractant cytokines) is due to their ability to induce directed chemotaxis in nearby responsive cells. Some CKs are considered proinflammatory and can be induced during an immune response to promote cells of the immune system to a site of infection. Furthermore, they have different functions under physiological conditions such as homoeostasis, development, tissue repair and angiogenesis and also in pathological disorders including infectious and autoimmune diseases, cancer, metastasis, allergic process and organ transplantation; in fact, in any situation where immune components are involved.

CKs are found in all vertebrates, some viruses and in some bacteria. These proteins exert their biological effects by interacting with G protein‐linked transmembrane receptors called CK receptors (CKRs) that are selectively found on the surfaces of their target cells.

Although their role in human immunodeficiency virus infection is still the main aspect of relevance, other applications have been appearing during the past years, as to establish new therapeutic compounds able to target the CK/CKR system.

Key Concepts:

  • Chemokines (CKs), as chemoattractant cytokines, are pivotal elements for defining immune cell localisation and, therefore, efficient immune responses.

  • Beyond their role in chemotaxis, CKs and their receptors develop several physiopathological functions: angiogenesis, haematopoiesis, growth regulation, embryologic development, evolution of tumours, etc.

  • CKs have three types of receptors: ‘classical’ G protein‐coupled receptors (GPCRs), decoy receptors and glycosaminoglycans (GAGs).

  • After activation, GPCRs become either partially or totally desensitised to repeated stimulation with the same or other agonists; desensitisation is critical for maintaining the capacity of the cell to sense a chemoattractant gradient.

  • Decoy receptors are ‘silent’ receptors that control the CK activity through regulation of CK levels in the body.

  • CK immobilisation through the GAG interaction stabilises the formation of CK gradients and enhances their concentration at the site of production.

  • All CKs have a common structure, being the first couple of cysteines (Cs) a distinctive element that allows classifying them into CC, CXC, CX3C and C CK families.

  • Most of the inflammatory CK genes are clustered in two main chromosomal regions: the CXC cluster, located in chromosome 4q12–21 and the CC cluster, located in chromosome 17q11.2.

  • The ‘evolutionary choice’ of HIV‐1 to exploit CKRs as cellular entry gateways has turned their CK ligands into endogenous antiviral factors that can variably modulate viral transmission, disease progression and vaccine responses.

Keywords: leucocyte; chemoattractant; recirculation; inflammation; HIV

Figure 1.

Chemokine–chemokine receptor structure and interaction. (a) Proposed general topography of the CCL4 CK. Amino acids forming the three β sheets and the α helix are depicted in orange and green, respectively. The two disulphide bridges that stabilise the tertiary structure are shown as red lines connecting the four Cs. (b) Proposed membrane topography of the human CCR5 receptor. Membrane‐spanning α helices are defined on the basis of hydropathy analysis. CHO represents potential N‐linked glycosylation sites. Residues shown in blue represent the DRYLAVHA sequence motif characteristic of CKRs. Residues in red represent Ser and Thr residues that are potential phosphorylation sites for specific receptor kinases during desensitisation. Note that the CCL4 N‐terminus interact with the extracellular part of CCR5 receptor.

Figure 2.

Proposed multistep mechanism of entry of HIV‐1 by interaction with CD4 and chemokine receptors.

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Juan, Manel, Pedrosa, Edurne, and Colobran, Roger(May 2013) Chemokines and Chemokine Receptors. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000933.pub3]