Disease relevance of CX3CL1

• Fractalkine (CX3CL1) is of particular interest in atherogenesis because it can serve as an adhesion molecule and a chemokine [1].
• The potential role of the chemokine Fractalkine (CX3CL1) in the pathophysiology of traumatic brain injury (TBI) was investigated in patients with head trauma and in mice after experimental cortical contusion [2].
• Up regulated expression of fractalkine/CX3CL1 and CX3CR1 in patients with systemic sclerosis [3].
• Fractalkine (CX3CL1) and brain inflammation: Implications for HIV-1-associated dementia [4].
• Characterization of fractalkine (CX3CL1) and CX3CR1 in human coronary arteries with native atherosclerosis, diabetes mellitus, and transplant vascular disease [5].

High impact information on CX3CL1

• Natural killer cells predominantly express CX3CR1 and respond to fractalkine in both migration and adhesion [6].
• Fractalkine, a novel transmembrane molecule with a CX3C-motif chemokine domain atop a mucin stalk, induces both adhesion and migration of leukocytes [6].
• Neurotactin messenger RNA is predominantly expressed in normal murine brain and its protein expression in activated brain microglia is upregulated in mice with experimental autoimmune encephalomyelitis, as well as in mice treated with lipopolysaccharide [7].
• Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation [7].
• Recombinant neurotactin containing the chemokine domain is chemotactic for neutrophils both in vitro and in vivo [7].

Chemical compound and disease context of CX3CL1

• The effects of AS-6 on TNF-alpha-stimulated VCAM-1 and CX3CL1 expression were abolished in cells transfected with an adenovirus expressing dominant-negative PPARgamma and in cells treated with a PPARgamma specific inhibitor, GW9662, confirming again that the anti-inflammatory effect of AS-6 was PPARgamma-dependent [8].
• Alterations in the expression of the chemokine, fractalkine (CX3CL1), were examined in the urinary bladder after cyclophosphamide (CYP)-induced cystitis of varying duration: acute (4 h or 48 h), or chronic (10 day) [9].
• Alpha-lipoic acid inhibits fractalkine expression and prevents neointimal hyperplasia after balloon injury in rat carotid artery [10].
• Moreover, FKN significantly reduced neuronal NMDA-induced apoptosis, which was pertussis toxin insensitive and abolished in presence of PD98059 and LY294002 [11].
• Application of FKN triggered a 53% reduction of the NMDA-induced neuronal calcium influx, which was insensitive to pertussis toxin and LY294002 an inhibitor of Akt pathway, but abolished by PD98059, an ERK1/2 pathway inhibitor [11].

Biological context of CX3CL1

• The CX3C chemokine fractalkine (CX3CL1) exists as a membrane-expressed protein promoting cell-cell adhesion and as a soluble molecule inducing chemotaxis [12].
• Consistent with previous reports, our data indicate that the activity of CX3CR1 on resting monocytes is sufficient to mediate cell adhesion to CX3CL1 [13].
• Fractalkine (CX3CL1), a chemotactic membrane-bound adhesion factor, and its receptor (CX3CR1) were assessed by immunohistochemistry in endometrial samples across the menstrual cycle, in early pregnancy, and in women using progestin-only contraceptives [14].
• We found that s-FKN fails to induce MonoMac6 cell migration per se [15].
• Chimeric and insertional mutagenesis was used to generate mutants of both vMIP-II and FKN, and the expressed proteins were evaluated for chemokine receptor binding affinities and efficacy at CX3CR1 [16].

Anatomical context of CX3CL1

• Using human pancreatic islets as an in vitro model of peripheral tissue, we showed that islet supernatants released factors able to attract BM-MSCs in vitro, and this attraction was principally mediated by CX3CL1 and CXCL12 [17].
• The membrane-anchored form of CX3CL1 has been proposed as a novel adhesion protein for leukocytes [13].
• Compatible with this hypothesis, stimulation of monocytes with MCP-1 significantly increased their adhesion to immobilized CX3CL1, under both static and physiological flow conditions [13].
• METHODS: Using flow cytometry, immunohistochemistry, and reverse transcription-polymerase chain reaction, we analyzed CX3CR1 expression by peripheral blood and synovial T cells, and CX3CL1 expression in synovium from patients with RA [18].
• Endometrial cell-conditioned media also stimulated trophoblast migration; this was attenuated by neutralizing antibodies to CX3CL1 and CCL4 [19].

Associations of CX3CL1 with chemical compounds

• Tumor necrosis factor-alpha-converting enzyme (ADAM17) mediates the cleavage and shedding of fractalkine (CX3CL1) [20].
• Interestingly, monocyte adhesion to CX3CL1-coated plates partially inhibited lipopolysaccharide-induced TF expression and TNF-alpha release [21].
• This release is inhibited by the zinc metalloproteinase inhibitor batimastat, resulting in the accumulation of membrane-associated fractalkine on the SMC surface [22].
• Modification of the intervening amino acids between the first two conserved cysteine residues of FKN or vMIP-II indicated a role of the X3 bulge of FKN in affinity and selectivity for CX3CR1 [16].
• Dexamethasone (10(-8)-10(-6) M) significantly upregulated cytokine-induced FKN mRNA and protein expression [23].
• This growth-promotion loop is amplified by TNFalpha produced by CX(3)CR1-expressing T cells upon stimulation by FKN-expressing FLS [24].

Physical interactions of CX3CL1

• In steady state experiments, all three CX3CR1 isoforms bound CX3CL1 with similar affinity [25].
• Fractalkine (CX3CL1) is a transmembrane molecule with a CX3C chemokine domain attached to an extracellular mucin stalk which can induce both adhesion and migration of leucocytes [26].

Co-localisations of CX3CL1

• VEGF colocalized with the expression of Fractalkine/CX3CR1 [27].

Regulatory relationships of CX3CL1

• Combined stimulation with IFN-gamma and TNF-alpha induced FKN mRNA and protein expression in a time- and concentration-dependent manner [23].
• RESULTS: Flow cytometric analysis of fractalkine-expressing T cell subsets revealed a low proportion of fractalkine-expressing CD4+ and CD8+ T cells in both RA patients and controls [28].
• There is a positive correlation between the number of fractalkine-expressing cells and the number of CX3CR1-positive cells in human atherosclerotic plaques (r=0.70, n=15 plaques) [29].
• Moreover, the membrane form of fractalkine expressed on ECV304 cells reduced MCP-1 mediated chemotaxis of THP-1 cells [30].
• Furthermore, we observed that s-FKN also inhibits the activity of a major matrix metalloproteinase (MMP), namely MMP-2 [15].

Other interactions of CX3CL1

• These results demonstrate that FKN preferentially mediates arrest and migration of CD16+ monocytes and suggest that recruitment of this proinflammatory monocyte subset to vessel walls via the CX3CR1-FKN pathway may contribute to vascular and tissue injury during pathological conditions [31].
• Inhibition of ADAM10-mediated CX3CL1 shedding not only increased adhesive properties of CX3CL1-ECV-304 cells but also prevented de-adhesion of bound THP-1 cells [12].
• High levels of MDC, TARC, and fractalkine mRNA expression are seen in some, but not all, human arteries with advanced atherosclerotic lesions [32].
• Unlike other human chemokines, the chemokine domain of fractalkine has three amino acids between two conserved cysteines, referred to as the CX3C motif [33].
• In this study, we address the question of the cross-talk between two chemokines that are cosecreted during inflammation, namely monocyte chemoattractant protein-1 (MCP-1) and soluble fractalkine (s-FKN), toward monocyte migration [15].

Analytical, diagnostic and therapeutic context of CX3CL1

• Cell-associated and shedded CX3CL1 were measured with a specific ELISA, showing that only 30% of the protein was cleaved from the membrane [21].
• METHODS AND RESULTS: Western blot analysis revealed that fractalkine protein was detected as a 95 kDa band in the isthmus, the ampulla and the infundibulum of the Fallopian tube [34].
• RT-PCR demonstrated that fractalkine transcripts were expressed in all parts of the Fallopian tube [34].
• Expression of fractalkine and its receptor was characterized in RA synovium by immunohistochemistry and laser capture microdissection microscopy [28].
• Recently, accumulating evidence has shown that fractalkine is involved in the pathogenesis of various clinical disease states or processes, such as atherosclerosis, glomerulonephritis, cardiac allograft rejection, and rheumatoid arthritis [35].

References