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      Polymorphism of the Fractalkine Receptor CX3CR1 and Systemic Sclerosis-associated Pulmonary Arterial Hypertension

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          Abstract

          Fractalkine (FKN) and its receptor CX3CR1 are critical mediators in the vascular and tissue damage of several chronic diseases, including systemic sclerosis (SSc) and pulmonary arterial hypertension (PAH). Interestingly, the V249I and T280M genetic polymorphisms influence CX3CR1 expression and function. We investigated whether these polymorphisms are associated with PAH secondary to SSc. CX3CR1 genotypes were analyzed by PCR and sequencing in 76 patients with limited SSc and 204 healthy controls. PAH was defined by colorDoppler echocardiography. Homozygosity for 249II as well as the combined presence of 249II and 280MM were significantly more frequent in patients with SSc compared to controls (17 vs 6%, p = 0.0034 and 5 vs 1%, p = 0.0027, respectively). The 249I and 280M alleles were associated with PAH (odd ratio [OR] 2.2, 95% confidence interval [CI] 1.01-4.75, p = 0.028 and OR 7.37, 95%CI: 2.45-24.60, p = 0.0001, respectively). In conclusion, the increased frequencies of 249I and 280M CX3CR1 alleles in a subgroup of patients with SSc-associated PAH suggest a role for the fractalkine system in the pathogenesis of this condition. Further, the 249I allele might be associated with susceptibility to SSc.

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          Fractalkine Preferentially Mediates Arrest and Migration of CD16+ Monocytes

          CD16+ monocytes represent 5–10% of peripheral blood monocytes in normal individuals and are dramatically expanded in several pathological conditions including sepsis, human immunodeficiency virus 1 infection, and cancer. CD16+ monocytes produce high levels of proinflammatory cytokines and may represent dendritic cell precursors in vivo. The mechanisms that mediate the recruitment of CD16+ monocytes into tissues remain unknown. Here we investigate molecular mechanisms of CD16+ monocyte trafficking and show that migration of CD16+ and CD16− monocytes is mediated by distinct combinations of adhesion molecules and chemokine receptors. In contrast to CD16− monocytes, CD16+ monocytes expressed high CX3CR1 and CXCR4 but low CCR2 and CD62L levels and underwent efficient transendo-thelial migration in response to fractalkine (FKN; FKN/CX3CL1) and stromal-derived factor 1α (CXCL12) but not monocyte chemoattractant protein 1 (CCL2). CD16+ monocytes arrested on cell surface–expressed FKN under flow with higher frequency compared with CD16− monocytes. 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.
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            Fractalkine and CX3CR1 Mediate a Novel Mechanism of Leukocyte Capture, Firm Adhesion, and Activation under Physiologic Flow

            Leukocyte migration into sites of inflammation involves multiple molecular interactions between leukocytes and vascular endothelial cells, mediating sequential leukocyte capture, rolling, and firm adhesion. In this study, we tested the role of molecular interactions between fractalkine (FKN), a transmembrane mucin-chemokine hybrid molecule expressed on activated endothelium, and its receptor (CX3CR1) in leukocyte capture, firm adhesion, and activation under physiologic flow conditions. Immobilized FKN fusion proteins captured resting peripheral blood mononuclear cells at physiologic wall shear stresses and induced firm adhesion of resting monocytes, resting and interleukin (IL)-2–activated CD8+ T lymphocytes and IL-2–activated NK cells. FKN also induced cell shape change in firmly adherent monocytes and IL-2–activated lymphocytes. CX3CR1-transfected K562 cells, but not control K562 cells, firmly adhered to FKN-expressing ECV-304 cells (ECV-FKN) and tumor necrosis factor α–activated human umbilical vein endothelial cells. This firm adhesion was not inhibited by pertussis toxin, EDTA/EGTA, or antiintegrin antibodies, indicating that the firm adhesion was integrin independent. In summary, FKN mediated the rapid capture, integrin-independent firm adhesion, and activation of circulating leukocytes under flow. Thus, FKN and CX3CR1 mediate a novel pathway for leukocyte trafficking.
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              CX(3)C chemokine fractalkine in pulmonary arterial hypertension.

              Perivascular infiltrates composed of macrophages and lymphocytes have been described in lung biopsies of patients displaying pulmonary arterial hypertension (PAH), suggesting that circulating inflammatory cells can be recruited in affected vessels. CX(3)C chemokine fractalkine is produced by endothelial cells and promotes leukocyte recruitment, but unlike other chemokines, it can capture leukocytes rapidly and firmly in an integrin-independent manner under high blood flow. We therefore hypothesized that fractalkine may contribute to pulmonary inflammatory cell recruitment in PAH. Expression and function of the fractalkine receptor (CX(3)CR1) were studied by use of triple-color flow cytometry on circulating T-lymphocyte subpopulations in freshly isolated peripheral blood mononuclear cells from control subjects and patients with PAH. Plasma-soluble fractalkine concentrations were measured by enzyme-linked immunosorbent assay. Finally, fractalkine mRNA and protein expression were analyzed in lung samples by reverse transcriptase-polymerase chain reaction or in situ hybridization and immunohistochemistry, respectively. In patients with PAH, CX(3)CR1 expression and function are upregulated in circulating T-lymphocytes, mostly of the CD4+ subset, and plasma soluble fractalkine concentrations are elevated, as compared with control subjects. Fractalkine mRNA and protein product are expressed in pulmonary artery endothelial cells. We conclude that inflammatory mechanisms involving chemokine fractalkine and its receptor CX(3)CR1 may have a role in the natural history of PAH.
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                Author and article information

                Journal
                Clin Dev Immunol
                Clinical and Developmental Immunology
                Hindawi Publishing Corporation
                1740-2522
                1740-2530
                December 2005
                : 12
                : 4
                : 275-279
                Affiliations
                [1 ] Rheumatology Unit Department of Medicine Surgery and Dentistry, Humanitas Clinical Institute University of Milan, Rozzano Milan Italy
                [2 ] Division of Internal Medicine San Paolo School of Medicine University of Milan Italy
                [3 ] Division of Rheumatology, Allergy, Clinical Immunology University of California Davis CA USA
                [4 ] Department of Medicine S. Gerardo Hospital Monza Italy
                [5 ] Clinical Chemistry Laboratory S. Paolo Hospital Milan Italy
                Article
                S1740252205000363
                10.1080/17402520500303297
                2270742
                16584113
                f45442f6-305d-449c-b3b4-23aefa8b3f92
                Copyright © 2005 Hindawi Publishing Corporation.

                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.

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                Research Article

                Immunology
                Immunology

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