Chemokine Signaling Pathway

Chemokines are small proteins, usually ~70–80 amino acid residues, with conserved sequence and structural features and expressed in tissues during normal immune surveillance or in response to injury or infection.

Chemokines are defined by their primary amino acid sequence and the arrangement of specific structurally important cysteine residues within the mature protein. Variation in the precise configuration of the two cysteines closest to the N terminus allows chemokines to be split into four subfamilies: CC, CXC, CX3C, and XC. In CC chemokines, these cysteines are directly juxtaposed, while CXC chemokines have a single variable amino acid between them. The sole CX3C chemokine has three amino acids between these two cysteines, while XC chemokines, of which there are two forms in humans and one in mice, lack the first and the third cysteines of the motif.

Chemokines are designated according to their subfamily classification by systematic names composed of a prefix (CCL, CXCL, CX3CL, or XCL; “L” signifies a ligand as opposed to a receptor) followed by an identifying number.

Chemokines bind and activate chemokine receptors, G protein-coupled receptors (GPCRs) embedded in the cell membranes of leukocytes, thereby inducing leukocyte adhesion to the vessel wall, morphological changes, extravasation into the inflamed tissue, and chemotaxis along the chemokine gradient to the site of injury or infection.

Mammalian genomes each encode approximately 20 chemokine receptors. Because the receptors were discovered after the chemokines and most of them are selective for members of one chemokine subfamily, they are classified according to the subfamily of chemokines to which most of their ligands belong. Thus, receptors are named using the prefixes CCR, CXCR, CX3CR, and XCR followed by an identifying number.

A given chemokine can stimulate different responses depending on the receptor to which it binds as well as on the cells where the receptors are expressed.

Chemokine signaling is essential for coordinated cell migration in health and disease to specifically govern cell positioning in space and time. Typically, chemokines signal through heptahelical GPCRs to orchestrate cell migration.

Different subsets of leukocytes express different arrays of chemokine receptors, enabling them to respond to the appropriate ligands. Most chemokines bind and activate several receptors. Similarly, most chemokine receptors respond to multiple chemokine ligands. This selectivity of recognition is an intrinsic property of the chemokine-receptor pair. However, selectivity can be altered by modification of the proteins

The interactions of chemokines with their G protein-coupled receptors promote the migration of leukocytes during normal immune function and as a key aspect of the inflammatory response to tissue injury or infection. Upon activation, GPCRs become desensitized through phosphorylation of their intracellular C-termini by second messenger–dependent kinases and GPCR kinases (GRKs). The phosphorylation pattern, also known as barcode, induces arrest in recruitment to the receptor.

Typically, chemokine receptor stimulation leads to the GDP/GTP exchange of coupled heterotrimeric Gi proteins and the subsequent dissociation of the βγ subunits, which then activate phosphoinositide-specific phospholipase Cβ (PLC) and phosphoinositide 3-kinase (PI3K). PLC produces inositol-trisphosphate (IP3) and diacylglycerol (DAG). IP3 triggers calcium mobilization whereas DAG activates protein kinase C (PKC). PI3K generates 3-phosphoinositides, which serve as anchors in the recruitment of proteins with pleckstrin homology domains to the plasma membrane, such as AKT/PKB. Although these signaling events are common to all chemokine receptors, it is well known that the activation of further downstream pathways is quite different. This may depend on the efficacy with which a chemokine triggers its receptor, giving rise to different spatial and temporal signal fluxes.

By far the most studied function of the chemokine network is cell migration, particularly of leukocytes. In addition to their roles in leukocyte trafficking, chemokine activation of chemokine receptors can give rise to a variety of additional cellular and tissue responses, including proliferation, activation, differentiation, extracellular matrix remodeling, angiogenesis, and tumor metastasis.

As recently reviewed elsewhere, a wide variety of other biological processes can be induced by the activation of cCKRs on leukocytes, including proliferation, survival, differentiation, cytokine production, degranulation, and respiratory burst. Moreover, several chemokines have direct antimicrobial activity. In addition, many nonleukocytic cell types, including neurons, astrocytes, epithelial cells, mesenchymal cells, and endothelial cells, can express cCKRs and respond in a wide variety of ways to chemokines

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