Chemokines and Chemokine Receptors

Manel Juan, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain
Edurne Pedrosa, Biobanc IGTP‐HUGTP, Badalona, Spain
Roger Colobran, Institut de Recerca Vall d'Hebron (VHIR), Barcelona, Spain

Published online: May 2013

DOI: 10.1002/9780470015902.a0000933.pub3

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.
close

References

Allegretti M, Cesta MC, Garin A and Proudfoot AEI (2012) Current status of chemokine receptor inhibitors in development. Immunology Letters 145: 68–78.

Auerbach DJ, Lin Y, Miao H et al. (2012) Identification of the platelet‐derived chemokine CXCL4/PF‐4 as a broad‐spectrum HIV‐1 inhibitor. Proceedings of the National Academy of Sciences of the USA 109: 9569–9574.

Balkwill F (2004) Cancer and the chemokine network. Nature Reviews Cancer 4: 540–550.

Benelli R, Barbero A, Buffa A et al. (2000) Distinct chemotactic and angiogenic activities of peptides derived from Kaposi's sarcoma virus encoded chemokines. International Journal of Oncology 17: 75–81.

Bernardini G, Gismondi A and Santoni A (2012) Chemokines and NK cells: regulators of development, trafficking and functions. Immunology Letters 145: 39–46.

Carvalho CM, Zhang F and Lupski JR (2010) Evolution in health and medicine Sackler colloquium: genomic disorders: a window into human gene and genome evolution. Proceedings of the National Academy of Sciences of the USA 107(Suppl. 1): 1765–1771.

Colobran R, Casamitjana N, Roman A et al. (2009) Copy number variation in the CCL4L gene is associated with susceptibility to acute rejection in lung transplantation. Genes and Immunity 10: 254–259.

Colobran R, Pedrosa E, Carretero‐Iglesia L and Juan M (2010) Copy number variation in chemokine superfamily: the complex scene of CCL3L‐CCL4L genes in health and disease. Clinical and Experimental Immunology 162: 41–52.

Chen HJ, Edwards R, Tucci S et al. (2012) Chemokine 25‐induced signaling suppresses colon cancer invasion and metastasis. Journal of Clinical Investigation 122: 3184–3196.

Colobran R, Pujol‐Borrell R, Armengol MP and Juan M (2007a) The chemokine network. I. How the genomic organization of chemokines contains clues for deciphering their functional complexity. Clinical and Experimental Immunology 148: 208–217.

Colobran R, Pujol‐Borrell R, Armengol MP and Juan M (2007b) The chemokine network. II. On how polymorphisms and alternative splicing increase the number of molecular species and configure intricate patterns of disease susceptibility. Clinical and Experimental Immunology 150: 1–12.

Comerford I and Nibbs RJ (2005) Post‐translational control of chemokines: a role for decoy receptors? Immunology Letters 96: 163–174.

Cook DN (1996) The role of MIP‐1 alpha in inflammation and hematopoiesis. Journal of Leukocyte Biology 59: 61–66.

Croudace JE, Inman CF, Abbotts BE et al. (2012) Chemokine‐mediated tissue recruitment of CXCR3+ CD4+ T‐cells plays a major role in the pathogenesis of chronic graft versus host disease. Blood doi:10.1182/blood-2012-02-413260.

Daley‐Bauer LP, Wynn MG and Mocarski ES (2012) Cytomegalovirus impairs antiviral CD8+ T cell immunity by recruiting inflammatory monocytes. Immunity 37: 122–133.

Förster R, Davalos‐Misslitz AC and Rot A (2008) CCR7 and its ligands: balancing immunity and tolerance. Nature Reviews Immunology 8: 362–371.

Gerard C and Rollins BJ (2001) Chemokines and disease. Nature Immunology 2: 108–115.

Hadeiba H, Sato T, Habtezion A et al. (2008) CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft‐versus‐host disease. Nature Immunology 9: 1253–1260.

Holgate ST (2012) Innate and adaptive immune responses in asthma. Nature Medicine 18: 673–683.

Homey B, Alenius H, Müller A et al. (2002) CCL27‐CCR10 interactions regulate T cell‐mediated skin inflammation. Nature Medicine 8: 157–165.

Hütter G, Nowak D, Mossner M et al. (2009) Long‐term control of HIV by CCR5 Delta32/Delta32 stem‐cell transplantation. New England Journal of Medicine 360: 692–698.

Kuhmann SE and Hartley O (2008) Targeting chemokine receptors in HIV: a status report. Annual Review of Pharmacology and Toxicology 48: 425–461.

Kunkel SL and Godessart N (2002) Chemokines in autoimmunity: from pathology to therapeutics. Autoimmunity Reviews 1: 313–320.

Langhi DM Jr and Bordin JO (2006) Duffy blood group and malaria. Hematology 11: 389–398.

Lusso P (2006) HIV and the chemokine system: 10 years later. EMBO Journal 25: 447–456.

Maerki C, Meuter S, Liebi M et al. (2009) Potent and broad‐spectrum antimicrobial activity of CXCL14 suggests an immediate role in skin infections. Journal of Immunology 182: 507–514.

Martínez‐Muñoz L, López‐Holgado B, Martínez AC, Rodríguez‐Frade JM and Mellado M (2012) Chemokine receptor oligomerization: a further step toward chemokine function. Immunology Letters 145: 23–29.

Medoff BD, Seung E, Hong S et al. (2009) CD11b+ myeloid cells are the key mediators of Th2 cell homing into the airway in allergic inflammation. Journal of Immunology 182: 623–635.

Melchjorsen J, Sørensen LN and Paludan SR (2003) Expression and function of chemokines during viral infections: from molecular mechanisms to in vivo function. Journal of Leukocyte Biology 74: 331–343.

Milligan ED, Sloane EM and Watkins LR (2008) Glia in pathological pain: a role for fractalkine. Journal of Neuroimmunology 198: 113–120.

Mori M, Liu D, Kumar S and Huang Z (2005) NMR structures of anti‐HIV D‐peptides derived from the N‐terminus of viral chemokine vMIP‐II. Biochemical and Biophysical Research Communications 335: 651–658.

Mortier A, Van Damme J and Proost P (2008) Regulation of chemokine activity by posttranslational modification. Pharmacology and Therapeutics 120: 197–217.

Mortier A, Van Damme J and Proost P (2012) Overview of the mechanisms regulating chemokine activity and availability. Immunology Letters 145: 2–9.

O'Boyle G, Fox CR, Walden HR et al. (2012) Chemokine receptor CXCR3 agonist prevents human T‐cell migration in a humanized model of arthritic inflammation. Proceedings of the National Academy of Sciences of the USA 109: 4598–4603.

Pedrosa E, Carretero‐Iglesia L, Boada A et al. (2011) CCL4L Polymorphisms and CCL4/CCL4L Serum Levels Are Associated with Psoriasis Severity. Journal of Investigative Dermatology 131: 1830–1837.

Proudfoot AE (2006) The biological relevance of chemokine–proteoglycan interactions. Biochemical Society Transactions 34: 422–426.

Proudfoot AE, Handel TM, Johnson Z et al. (2003) Glycosaminoglycan binding and oligomerization are essential for the in vivo activity of certain chemokines. Proceedings of the National Academy of Sciences of the USA 100: 1885–1890.

Rankin SM (2012) Chemokines and adult bone marrow stem cells. Immunology Letters 145: 47–54.

Reshef R, Luger SM, Hexner EO et al. (2012) Blockade of lymphocyte chemotaxis in visceral graft‐versus‐host disease. New England Journal of Medicine 367: 135–145.

Springael JY, Urizar E and Parmentier M (2005) Dimerization of chemokine receptors and its functional consequences. Cytokine and Growth Factor Reviews 16: 611–623.

Stievano L, Piovan E and Amadori A (2004) C and CX3C chemokines: cell sources and physiopathological implications. Critical Reviews in Immunology 24: 205–228.

Strieter RM, Burdick MD, Gomperts BN, Belperio JA and Keane MP (2005) CXC chemokines in angiogenesis. Cytokine and Growth Factor Reviews 16: 593–609.

Szczuciński A and Losy J (2007) Chemokines and chemokine receptors in multiple sclerosis. Potential targets for new therapies. Acta Neurologica Scandinavica 115: 137–146.

Tachibana K, Hirota S, Iizasa H et al. (1998) The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393: 591–594.

Vischer HF, Vink C and Smit MJ (2006) A viral conspiracy: hijacking the chemokine system through virally encoded pirated chemokine receptors. Current Topics in Microbiology and Immunology 303: 121–154.

Yang D, Chen Q, Hoover DM et al. (2003) Many chemokines including CCL20/MIP‐3alpha display antimicrobial activity. Journal of Leukocyte Biology 74: 448–455.

Yang LL, Ping C, Luo S et al. (2009) CXCL10 gene therapy efficiently inhibited the growth of cervical carcinoma based on the antiangiogenic and antiviral activity. Biotechnology and Applied Biochemistry 53: 209–216.

Yeganeh B, Xia C, Movassagh H et al. (2012) Emerging mediators of airway smooth muscle dysfunction in asthma. Pulmonary Pharmacology and Therapeutics. http://dx.doi.org/10.1016/j.pupt.2012.06.011.

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

Further Reading

Boomker JM, de Leij LF, The TH and Harmsen MC (2005) Viral chemokine‐modulatory proteins: tools and targets. Cytokine and Growth Factor Reviews 16: 91–103.

Fulton A (ed.) (2009) Chemokine Receptors in Cancer. Totowa, NJ: Humana Press.

Mahalingam S (2004) Chemokines in Viral Infections. Austin, TX: Landes Bioscience.

Oppenheim J and Feldman M (2001) Cytokine Reference: Volume 1 and Volume 2. San Diego, CA: Academic Press.

Raman D, Sobolik‐Delmaire T and Richmond A (2011) Chemokines in health and disease. Experimental Cell Research 317: 575–589.

Schwiebert L, Benos D and Simon S (2005) Chemokines, Chemokine Receptors and Disease. San Diego, CA: Academic Press.

Vaddi K, Keller M and Newton RC (1997) The Chemokine Factsbook. San Diego, CA: Academic Press.

Zlotnik A and Yoshie O (2012) The chemokine superfamily revisited. Immunity 36: 705–716.

Related Sub-Topics:

Proteins: Structure, Function, Metabolism | Cytokines
Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

Article Title: Chemokines and Chemokine Receptors
 
How to Cite close
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]