Fractalkine: A Survivor's Guide

Abstract

Abstract-Chemokines are a family of low-molecular-weight proteins essential to the directed migration of cells under homeostatic and pathological conditions. Fractalkine (CX3CL1) is an unusual chemokine that can act as either a soluble or membrane-bound mediator and signals through the G protein-coupled chemokine receptor CX3CR1, expressed on monocytes, natural killer cells, T cells, and smooth muscle cells. Accumulating evidence suggests that fractalkine, in addition to its role in chemotaxis and adhesion of leukocytes, supports the survival of multiple cell types during homeostasis and inflammation. This review presents the evidence obtained from several disease models implying an antiapoptotic function for fractalkine and shows how this is relevant to the pathology of atherosclerosis and other vascular diseases. We discuss whether the key role of fractalkine, unlike other chemokines, is the promotion of cell survival and whether this has implications for vascular disease. (Arterioscler Thromb Vasc Biol. 2012;32:589-594.)Key Words: apoptosis Ⅲ atherosclerosis Ⅲ macrophages Ⅲ vascular biology Ⅲ chemokines F irst recognized in 1987 with the discovery of interleukin-8, the chemokine family today numbers at least 46 members divided into 4 families on the basis of structure. 1,2 As their name-chemotactic cytokinessuggests, all members of the family share the ability to chemoattract cells expressing their cognate G protein-coupled receptors. The variety of cellular functions ascribed to chemokines is vast and growing, including adhesion, proliferation, survival, angiogenesis, and regulation of proinflammatory gene expression. In addition, chemokine receptor expression has been described for virtually every cell type studied, under both homeostatic and inflammatory conditions. Dysregulation of chemokine and chemokine receptor expression is associated with multiple disease states, including cardiovascular disease, cancer, neurodegenerative disease, and systemic inflammatory disease, such as rheumatoid arthritis and systemic lupus erythematosus (reviewed in 3 ).Fractalkine (CX3CL1) is the only member of the CX3C chemokine family and is expressed as a membrane-bound molecule with the chemokine domain attached via a mucinlike stalk to the cell surface. 4 A recent analysis of fractalkine expression using a Cx3cl1 cherry :Cx3cr1 gfp knock-in mouse identified neurons and epithelial cells in the lung, kidney, and intestine as the major sites of fractalkine expression, confirming previous reports. 5,6 Fractalkine can also be expressed by endothelial and smooth muscle cells under inflammatory conditions. 7,8 Cleavage at the base of the mucin stalk is mediated by at least 2 enzymes, ADAM10 and ADAM17, which function under homeostatic and inflammatory conditions, respectively. 9 -11 The structure of membrane-bound and soluble fractalkine is presented in Figure 1. Fractalkine is the unique ligand for the chemokine receptor CX3CR1, which is expressed on monocytes, natural killer cells, T cells, and smooth muscle cells, 12,13 where...

CX3CR1-dependent renal macrophage survival promotes Candida control and host survival

“…The fractalkine-Cx3cr1 axis has been reported to mediate survival of rat microglia and rat and human smooth muscle cells via different mechanisms, which all involve PI3K-dependent Akt activation (22,24,26,27). In agreement, Akt phosphorylation was reduced in sorted Cx3cr1 -/-kidney macrophages ( Figure 6H).…”

Do not let death do us part: ‘find-me’ signals in communication between dying cells and the phagocytes

“…83 In addition to increasing phagocytosis, FKN has also been associated with anti-inflammatory actions such as providing neuroprotection during glutamate toxicity, 84,85 modulating TNF-α secretion by microglia, 86 and promoting proliferative effects, 87,88 which may all have important roles in different settings of cell clearance. However, clarification is needed as to which processed form is responsible for these FKN effects.…”

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“…Unlike most chemokine ligands that demonstrate affinity for multiple receptors, CX3CL1 interacts with a single receptor. CX3CR1 is expressed on monocytes, natural killer cells, T cells, and smooth muscle cells, where it mediates migration, adhesion and proliferation [20] . Promotion of cell survival is considered another key function of CX3CL1 operating under both homeostatic and inflammatory conditions [20] .…”