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Chemokines

 

The chemokine family

 

The in vivo migration and navigation of leukocytes is carefully regulated to ensure the correct temporal and spatial positioning of cells and these processes are regulated, in the main, by members of the chemokine (chemotactic cytokine) family of peptides(1). Chemokines are a vertebrate 'invention' and the most ancient chemokine, almost certainly, is CXCL12(2). It is likely that the primordial role for CXCL12 was to regulate stem cell migration during early vertebrate embryogenesis(3, 4). This function has been conserved through evolution and the migration of a range of important stem cell types in embryonic and adult humans is also regulated by CXCL12(5, 6). From this single chemokine, through processes of gene duplication, the chemokine family has now evolved to the point where humans have almost 45 different chemokines which are involved, in sometimes very subtle ways, in regulating in vivo leukocyte migration.

 

 

 

The defining hallmark of the chemokine family

 

Membership of the chemokine family is strictly defined by the presence of variations on a conserved cysteine motif in the mature sequence of the chemokines and chemotactic proteins not containing this cysteine motif are not incorporated into the chemokine family.  The large chemokine family is subdivided into the CC (28 members), CXC (17 members), XC (1 member) and CX3C (1 member) subfamilies according to the specific nature of the cysteine motif (see the figure below). This cysteine motif is essential for the proper folding and function of chemokines which is why it has been so strongly conserved through evolution.

 

 

Cysteine motifs in chemokine receptors

 

 

 

 

 

 

 

 

 

Chemokines function in inflamed and homeostatic context

 

Chemokines can act as regulators of either inflammatory or homeostatic leukocyte migration(7, 8).  Thus inflammatory chemokines (such as CCL2, 3, 4 and 5) control the movement of inflammatory cells to sites of damage or infection. Inflammatory chemokines are not normally expressed at high levels but are induced rapidly, following tissue insult or injury, and help to recruit inflammatory leukocytes to any inflamed or infected sites. In contrast, the homeostatic chemokines (such as CCL19, 21, 25, 27) are expressed at low levels, and in very specific tissue locales, and are mainly involved in directing the basal trafficking of leukocytes to specific peripheral tissues and secondary lymphoid organs. The leukocyte migration driven by the homeostatic chemokines is therefore more subtle than that driven by the inflammatory ones.

 

 

Chemokines bind to GPCRs

 

Chemokines mediate their effects via receptors that belong to the seven- transmembrane spanning (7TM) family of proteins that are typically coupled to G-proteins for signalling(9).  There are 10 signalling receptors for the CC chemokines (CCRs1-10), 7 for the CXC chemokines (CXCRs1-7) and single receptors for the XC and CX3C chemokines(10). Again the receptors can be classified as being inflammatory or homeostatic according to the in vivo contexts in which they function and the ligand binding profiles of both classes of receptor are now well-characterised. 

 

The inflammatory receptors display marked promiscuity of ligand binding, for example CCR3 can bind up to 15 CC-chemokines and CCR5 binds CCL3, 4, 5 and 8 with high affinity.  In turn, each of these ligands is unfaithful to their receptors with CCL3, for example, showing high affinity binding to CCRs1, 3 and D6 (see below).  It is presumed that this apparent redundancy of receptor and ligand function in inflammation is important for ensuring a robust innate immune response to tissue insult. One clear consequence of this complex biology is that it has made understanding the orchestration of inflammatory responses very difficult!

 

In contrast to the inflammatory receptors the homeostatic receptors are characterised by more restricted ligand binding profiles and by the relatively restricted receptor usage of the ligands. Homeostatic receptors typically bind one, or at most two, ligands and the ligands are faithful to these receptors.  It is presumed that this more restricted receptor/ligand interaction is important for ensuring targeted and precise navigation of cells bearing these receptors.

 

 

Atypical chemokine receptors

 

The identification and analysis of the 'atypical' chemokine receptors is a prime interest of CRG. It has become apparent over the past few years that, in addition to the classical signalling chemokine receptors, there exists a smaller family of atypical chemokine ‘receptors’ the functions for which are currently being elucidated by us and others(11-13). This family includes the Duffy Antigen Receptor for Chemokines (DARC)(14), D6(15, 16) and CCXCKR/CCRL1 (formerly known as CCR11)(17) and also incorporates CXCR7.  A number of features set these molecules aside as being atypical but perhaps the most striking feature is that with DARC, D6 and CCXCKR it has been extremely difficult to demonstrate signalling responses to ligand and published evidence demonstrates that signalling mediated through CXCR7 is quite different from that mediated through the other classical chemokine receptors. These receptors are therefore referred to as 'atypical' chemokine receptors.  The ligand binding profiles of these receptors are shown below:

 

 

 

 

Ligands for the 'atypical' chemokine receptors

 

 

 

 

 

 

 

 

 

 

 

References

1.         Rot, A., and von Andrian, U.H. (2004) Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu Rev Immunol 22:891-928.

 

2.         Zlotnik, A., Yoshie, O., and Nomiyama,H. (2006) The chemokine and chemokine receptor superfamilies and their molecular evolution. Genome Biol 7:243.

 

3.         Doitsidou, M., Reichman-Fried, M.,Stebler, J., Koprunner, M., Dorries, J., Meyer, D., Esguerra, C.V., Leung, T.,and Raz, E. (2002)Guidance of primordial germ cell migration by the chemokine SDF-1. Cell 111:647-659.

 

4.         Boidajipour, B., Mahabaleshwar, H.,Kardash, E., Reichman-Fried, M., Blaser, H., Minina, S., Wilson, D., Xu, Q.L.,and Raz, E. (2008) Control of chemokine-guided cell migration by ligand sequestration. Cell 132:463-473.

 

5.         Lapidot, T., Dar, A., and Kollet, O.(2005) How do stem cells find their way home? Blood 106:1901-1910.

 

6.         Whetton, A.D., and Graham, G.J. (1999) Homing and mobilization in the stem cell niche. Trends Cell Biol 9:233-238.

 

7.         Mantovani, A. (1999) The chemokine system: redundancy for robust outputs. Immunol Today 20:254-257.

 

8.         Zlotnik, A., and Yoshie, O. (2000) Chemokines: a new classification system and their role in immunity. Immunity 12:121-127.

 

9.         Murphy, P.M., Baggiolini, M., Charo,I.F., Hebert, C.A., Horuk, R., Matsushima, K., Miller, L.H., Oppenheim, J.J.,and Power, C.A. (2000) International union of pharmacology. XXII. Nomenclature for chemokine receptors. Pharmacol Rev 52:145-176.

 

10.       Nomiyama, H., Osada, N., and Yoshie, O.(2011) A family tree of vertebrate chemokine receptors for a unified nomenclature.Developmental and Comparative Immunology 35:705-715.

 

11.       Graham, G.J. (2009) D6 and the atypical chemokine receptor family: novel regulators of immune and inflammatory processes. Eur J Immunol 39:342-351.

 

12.       Graham, G.J., Locati, M., Mantovani, A.,Rot, A., and Thelen, M. (2012) The biochemistry and biology of the atypical chemokine receptors. Immunology letters 145:30-38.

 

13.       Mantovani, A., Bonecchi, R., and Locati,M. (2006) Tuning inflammation and immunity by chemokine sequestration: decoys and more. Nat Rev Immunol 6:907-918.

 

14.       Rot, A. (2005) Contribution of Duffy antigen to chemokine function. Cytokine Growth Factor Rev 16:687-694.

 

15.       Graham, G.J., and Locati, M. (2013) Regulation of the immune and inflammatory responses by the 'atypical' chemokine receptor D6. Journal of Pathology 229:168-175.

 

16.       Lee, K.M., Nibbs, R.J.B., and Graham,G.J. (2013) D6: the 'crowd controller' at the immune gateway. Trends in Immunology 34:7-12.

 

17.       Comerford, I., Litchfield, W.,Harata-Lee, Y., Nibbs, R.J., and McColl, S.R. (2007) Regulation of chemotactic networks by 'atypical' receptors. Bioessays 29:237-247.