Editorial [Hot Topic: The Chemokine Network as Therapeutic Target in Human Diseases (Guest Editor: Luciano Ottonello)]

In 1987, three different groups described a novel tissue derived polypeptide capable of inducing migration of neutrophils, which was then named interleukin 8. A few years later, its receptor, which belongs to the seventransmembrane domain G protein-coupled (GPC) receptor family, was identified and cloned. These were the starting points leading to the identification of at least 47 components of a new structurally related superfamily of chemotactic cytokines named chemokines, and their 18 cognate receptors. Chemokines consist of 70 to 130 amino acids with four conserved cysteines. The cysteines form two disulphide bonds which confer to the chemokines their characteristic three-dimensional folding. The disulphides keep two amino-terminal regions together that are essential for receptor recognition and biological activity. Two main subfamilies are distinguished according to the position of the first two cysteines. CXC chemokines comprise 16 molecules, characterized by two cysteines separated by one aminoacid. CXC chemokines can be subdivided in two subfamilies, i.e. those containing the glutamic acid-leucine-arginine (ELR) sequence and those that do not. In particular, CXC-ELR+ chemokines are considered the main activators of neutrophil recruitment to sites of inflammation. CC chemokines include 28 ligands characterized by adjacent cysteines. Mononuclear cells and eosinophils are the preferential targets for CC chemokines, which in turn are generally inactive on neutrophils. Two variants of the chemokine structure paradigm have been described. Lymphotactins (α and β) with only two conserved cysteines (XC), and fractalkine, a membrane-bound mucin bearing three amino acids between the first two cysteines (CX3C). To date, six CXC receptors (CXCR1-6), ten CC receptors (CCR1-10), one CX3C receptor (CX3CR1) and one C receptor (XCR1) have been described. It is now clear that cells involved in the immune response are specifically and selectively recruited at site of inflammation also by means of their chemokine receptor expression, which is determined by the activation state of the cell, and by the pattern of the tissue chemokine expression. Originally identified for their chemoattractant properties, it is becoming increasingly apparent that chemokines exhibit critical functions in many diverse developmental and immunological operations ranging from the regulation of hematopoiesis and angiogenesis to the regulation of tissue architecture and organogenesis. More strikingly, several recent reports suggest that the chemokine-chemokine receptor system is deeply involved in HIV infection regulation, in a number of systemic and organ-specific autoimmune inflammatory diseases, in atherosclerosis as well as in allergic responses, in the development and dissemination of cancer as well as the host response to the neoplastic disease. GPC receptors, including chemokine receptors, are one of the most fruitful targets for pharmacological manipulation. Thus, interfering with the chemokine-chemokine receptor system seems to be a promising therapeutic strategy for a wide spectrum of pathological states in which this system is involved. Indeed, selective antagonists have been identified for the major chemokine receptors useful for the development of drug programs, and clinical trials. In this issue, researchers involved in the study of different diseases report the most recent advances on the pathophysiology of the chemokine-chemokine receptor system as a possible rationale target for an anti-chemokine-based therapeutic approach to the disease.