Role of Fractalkine/CX3CL1 and Its Receptor in the Pathogenesis of Inflammatory and Malignant Diseases with Emphasis on B Cell Malignancies

Hindawi Publishing Corporation Mediators of Inflammation Volume 2014, Article ID 480941, 10 pages http://dx.doi.org/10.1155/2014/480941 Review Article Role of Fractalkine/CX3CL1 and Its Receptor in the Pathogenesis of Inflammatory and Malignant Diseases with Emphasis on B Cell Malignancies Elisa Ferretti, Vito Pistoia, and Anna Corcione Laboratory of Oncology, Istituto Giannina Gaslini, 16147 Genova, Italy Correspondence should be addressed to Elisa Ferretti; Received 20 December 2013; Revised 26 February 2014; Accepted 5 March 2014; Published 30 March 2014 Academic Editor: Teizo Yoshimura Copyright © 2014 Elisa Ferretti et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Fractalkine/CX3CL1, the only member of the CX3C chemokine family, exists as a membrane-anchored molecule as well as in soluble form, each mediating different biological activities. It is constitutively expressed in many hematopoietic and nonhematopoietic tissues such as endothelial and epithelial cells, lymphocytes, neurons, microglial osteoblasts. The biological activities of CX3CL1 are mediated by CX3CR1, that is expressed on different cell types such as NK cells, CD14+ monocytes, cytotoxic effector T cells, B cells, neurons, microglia, smooth muscle cells, and tumor cells. The CX3CL1/CX3CR1 axis is involved in the pathogenesis of several inflammatory cancer including various B cell malignancies. In tumors the interaction between cancer cells and cellular microenvironment creates a context that may promote tumor growth, increase tumor survival, and facilitate metastasis. Therefore the role of the CX3CL1/CX3CR1 has attracted interest as to the development of potential therapeutic approaches. Here we review the different effects of the CX3CL1/CX3CR1 axis in several inflammatory and neurodegenerative diseases and in cancer, with emphasis on human B cell lymphomas. 1. Introduction Chemokines are small cytokines known for their ability to induce migration of cells such as lymphocytes, dendritic cells (DC), macrophages, and stem cells. Based on the cellular context and the site of expression, chemokines can be divided into “inflammatory chemokines,” that are synthesized and promote recruitment of cells during inflammation and “homeostatic chemokines,” that are constitutively expressed in specific tissues where they regulate leukocyte homing [1, 2]. Some chemokines participate both in immune defense during inflammation and in physiological trafficking of resting leukocytes [1, 2]. Moreover, some inflammatory chemokines are crucial components of tumor microenvironment and have a pivotal role in tumor progression, enhancing cancer cell migration to distant organs [3]. Chemokines are structurally characterized by a “chemokine scaffold,” that is, a conserved protein structure, dependent on two disulfide bonds linking cysteine residues. Based on the relative position of their cysteine residues located in the N-terminal region, chemokines can be divided into four subfamilies, CXC, CC, C, and CX3C [1, 2]. CXC chemokines can be further subdivided depending on the presence or absence of an ELR (Glu, Leu, and Arg) amino acid motif. ELR+ CXC chemokines attract neutrophils and possess angiogenic properties, whereas ELR− CXC chemokines are angiostatic and attract T and B lymphocytes as well as natural killer (NK) cells [4]. CC chemokines promote the migration of monocytes, DC, lymphocytes, eosinophils, and basophils. Lymphotactin/XCL1 and fractalkine/CX3CL1 are the only members of the C and CX3C chemokine families, respectively. Lymphotactin attracts T and B lymphocytes and NK cells, whereas fractalkine attracts predominantly T and B lymphocytes, NK cells, and monocytes [1, 2]. Chemokines mediate their functions through binding to seven transmembrane G-protein-coupled receptors defined as CXCR, CCR, CR, or CX3CR [1, 2]. Furthermore, some chemokines bind to multiple receptors and some receptors recognize more than one chemokine. 2 CX3CL1 consists of a chemokine domain linked to a transmembrane domain via an extended mucin-rich stalk of an extracellular domain. The chemokine is synthesized as membrane-anchored form and may be cleaved in the soluble form by different metalloprotease. [5, 6]. The membraneanchored CX3CL1 form functions as an adhesion molecule promoting retention of leucocytes to endothelial cells under physiological flow conditions [7]. The soluble CX3CL1 form is released following constitutive shedding operated by A Disintegrin And Metalloprotease (ADAM)10, whereas shedding under inflammatory conditions is mediated primarily by ADAM17 [8, 9]. CX3CL1 cleavage is also mediated by the lysosomal cysteine protease Cathepsin S [10]. Soluble CX3CL1 resembles a conventional chemokine exhibiting efficient chemotactic activity for human monocytes, NK cells, T cells, dendritic cells and, as demonstrated by our group, for a subset of germinal center B cells [5, 11]. CX3CL1 expression has been reported in many cell types of hematopoietic or nonhematopoietic origin, such as endothelial and epithelial cells, lymphocytes, neurons, microglial cells, and osteoblasts [12]. CX3CL1-driven chemotaxis and adhesion are mediated by CX3CR1 that is expressed on different cell types such as NK cells, CD14+ monocytes, cytotoxic effector T cells, B cells, neurons, microglia, smooth muscle cells, and tumor cells [11, 13–15]. CX3CL1 is involved in leukocyte recruitment associated with numerous inflammatory disorders and in tumorigenesis process in which the chemokine show pro- and antitumoral properties. The different roles of CX3CL1 make it an attractive candidate for the development of therapeutic strategies. This review will summarize the multiple roles of the CX3CL1/CX3CR1 axis in the pathogenesis of inflammation and cancer. 2. CX3CL1 in Inflammation Chemokines and adhesion molecules provide signals for trafficking, adhesion, and migration of leukocytes at sites of injury and inflammation [16]. In this context, CX3CL1 promotes the accumulation of immune cells that express CX3CR1, generating a vascular gateway for cytotoxic effector cells and being detrimental in several inflammatory diseases [6, 17, 18]. Increased levels of soluble CX3CL1 have been detected in serum, bronchoalveolar lavage fluids, and supernatants from airway smooth muscle cells, lung endothelium, and airway epithelium of allergic asthma and rhinitis patients. Both high secretion of CX3CL1 and upregulation of CX3CR1 function by naı̈ve and memory CD4+ T cells play a critical role in the recruitment of inflammatory cells after allergen stimulation [19, 20]. It has been demonstrated that transfer of CD4+ T cells from wild type mice into CX3CR1 deficient mice restores the clinical features of asthma, highlighting the therapeutic potential of the CX3CL1/CX3CR1 axis [21]. Rheumatoid arthritis (RA) i (...truncated)