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The skin is an organ in which the migration, influx, and egress of leukocytes occur in both homeostatic and inflammatory processes. Chemokines and their receptors are accepted as vital mediators of cellular trafficking. Since the discovery of the first chemoattractant cytokine or chemokine in 1977, 50 additional new chemokines and 17 chemokine receptors have been discovered. Most chemokines are small proteins with molecular weights in the 8–10 kDa range and are synthesized constitutively in some cells and can be induced in many cell types by cytokines. Initially associated only with recruitment of leukocyte subsets to inflammatory sites,1 it has become clear that chemokines play roles in angiogenesis, neural development, cancer metastasis, hematopoiesis, and infectious diseases. This chapter will focus primarily on the function of chemokines in inflammatory conditions, but will also touch upon the role of these molecules in other settings as well.
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An overview of the structure of chemokines and chemokine receptors will be provided that will detail the molecular signaling pathways initiated by the binding of a chemokine to its cognate receptor. Expression patterns of chemokine receptors will be detailed because of the many types of immune cells that potentially can be recruited to skin under inflammatory conditions. Individual chemokine receptors will be highlighted in regard to biologic function, including facilitation of migration of effector T cells into the skin and the egress of antigen-presenting cells out of the skin. Finally, the roles of chemokines and their receptors in several cutaneous diseases—atopic dermatitis, psoriasis, cancer, and infectious disease—provide a better idea of the diversity of chemokine function in skin.
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Chemokines are grouped into four subfamilies based on the spacing of amino acids between the first two cysteines. The CXC chemokines (also called α-chemokines) show a C–X–C motif with one nonconserved amino acid between the two cysteines. The other major subfamily of chemokines lacks the additional amino acid and is termed the CC subfamily (or β-chemokines). The two remaining subfamilies contain only one member each: the C subfamily is represented by lymphotactin, and fractalkine is the only member of the CXXXC (or CX3C) subfamily. Chemokines can also be assigned to one of two broad and, perhaps, overlapping functional groups. One group (e.g., RANTES, MIP-1α/β LARC, etc.) mediates the attraction and recruitment of immune cells to sites ...