Prevention of crescentic glomerulonephritis by immunoneutralization of the fractalkine receptor CX3CR1: Rapid Communication

Li, Feng; Chen, Shizhong; García, Georgia Earnest; Xia, Ying; Siani, Mike A.; Botti, Paulo; Wilson, Curtis B.; Harrison, Jeffrey K.; Bacon, Kevin B.

doi:10.1046/j.1523-1755.1999.00604.x

Cited by 180 publications

(167 citation statements)

References 38 publications

(5 reference statements)

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“…In the kidney, an important role for CX 3 CL1 has been found in diseases that involve glomerular inflammation and endothelial injury (19,20,22,23). CX 3 CL1 also is upregulated in renal tubulointerstitial inflammation, most notably in acute allograft rejection (19), but the specific localization of the chemokine (apical versus basolateral) has been somewhat unclear (32).…”

Section: Discussionmentioning

confidence: 99%

Expression and Targeting of CX3CL1 (Fractalkine) in Renal Tubular Epithelial Cells

Durkan¹,

Alexander²,

Liu³

et al. 2007

Journal of the American Society of Nephrology

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The chemokine CX 3 CL1 plays a key role in glomerulonephritis and can act as both chemoattractant and adhesion molecule. CX 3 CL1 also is upregulated in tubulointerstitial injury, but little is known about the subcellular distribution and function of CX 3 CL1 in renal tubular epithelial cells (RTEC). Unexpectedly, it was found that CX 3 CL1 is expressed predominantly on the apical surface of tubular epithelium in human renal transplant biopsy specimens with acute rejection or acute tubular necrosis. For studying the targeting of CX 3 CL1 in polarized RTEC, MDCK cells that expressed untagged or green fluorescent protein-tagged CX 3 CL1 were generated. The chemokine was present on the apical membrane and in subapical vesicles. Apical targeting of CX 3 CL1 was not due to signals that were conferred by its intracellular domain, to associations with lipid rafts, or to O-glycosylation but, rather, depended on N-linked glycosylation of the protein. With the use of fluorescence recovery after photobleaching, it was found that CX 3 CL1 is immobile in the apical membrane. However, CX 3 CL1 partitioned with the triton-soluble rather than -insoluble cellular fraction, indicating that it is not associated directly with the actin cytoskeleton or with lipid rafts. Accordingly, disruption of rafts through cholesterol depletion did not render CX 3 CL1 mobile. For exploration of potential functions of apical CX 3 CL1, binding of CX 3 CR1-expressing leukocytes to polarized RTEC was examined. Leukocyte adhesion to the luminal surface was enhanced significantly when CX 3 CL1 was present. These data demonstrate that CX 3 CL1 is expressed preferentially on the apical membrane of RTEC and suggest a novel function for the chemokine in recruitment and retention of leukocytes in tubulointerstitial inflammation.

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Section: Discussionmentioning

confidence: 99%

Expression and Targeting of CX3CL1 (Fractalkine) in Renal Tubular Epithelial Cells

Durkan¹,

Alexander²,

Liu³

et al. 2007

Journal of the American Society of Nephrology

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“…Endothelial cells upregulate the expression of both these molecules in response to TNF, IL-1 and LPS [33][34][35][36]40]. In addition, VCAM-1 and fractalkine are expressed in many of the same inflammatory diseases, including murine models of cardiac allograft rejection [19,41,42], crescentric nephritis [20,43] and experimental autoimmune encephalomyelitis [21,22,44]. Blockade of fractalkine-CX 3 CR1 interactions is beneficial in a murine model of crescentric glomerulonephritis [20].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, VCAM-1 and fractalkine are expressed in many of the same inflammatory diseases, including murine models of cardiac allograft rejection [19,41,42], crescentric nephritis [20,43] and experimental autoimmune encephalomyelitis [21,22,44]. Blockade of fractalkine-CX 3 CR1 interactions is beneficial in a murine model of crescentric glomerulonephritis [20]. Similarly, CX 3 CR1-deficient mice show prolonged survival following cardiac allograft [19].…”

Section: Discussionmentioning

confidence: 99%

“…However, it is the membrane-bound form that has generated the most interest as it potentially combines the direct action of an adhesion molecule with the specificity of a chemokine. Membrane-bound fractalkine is highly expressed in a number of murine models of inflammatory disease including cardiac allograft rejection [19], crescentric glomerulonephritis [20], and experimental autoimmune encephalomyelitis [21,22], as well as in the human inflammatory diseases rheumatoid arthritis [23], psoriasis [24] and atherosclerosis [25]. It is therefore very important to understand the mechanisms by which this chemokine may contribute to disease processes.…”

Section: Introductionmentioning

confidence: 99%

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Human fractalkine mediates leukocyte adhesion but not capture under physiological shear conditions; a mechanism for selective monocyte recruitment

et al. 2003

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Fractalkine is a unique chemokine possessing a long mucin-like stalk and a transmembrane region that has been proposed to act as an adhesion molecule. We investigated the ability of fractalkine to recruit leukocytes from whole blood, using an immobilized fractalkine fusion protein in the parallel-plate flow-chamber assay. Significant adhesion of leukocytes to fractalkine peaked at 2 dynes/cm 2 but was minimal at 10 dynes/cm 2 . In contrast, VCAM-1 could recruit cells from whole blood at 10 dynes/cm 2 . Co-immobilization of fractalkine and VCAM-1 at 10 dynes/cm 2 resulted in a twofold increase in adherent cells compared with VCAM-1 alone, suggesting that fractalkine can mediate adhesion at high shear if combined with a molecule that can mediate leukocyte tethering. Pretreatment of blood with pertussis toxin eliminated this increase in adhesion, implicating intracellular signaling in fractalkinemediated mechanisms of adhesion to co-immobilized fractalkine/VCAM-1. Analysis of the cell types recruited to fractalkine alone at low shear, or to fractalkine and VCAM-1 at 10 dynes/cm 2 , revealed that monocytes were recruited to fractalkine with the highest specificity. In conclusion, fractalkine is unlikely to act alone at shear forces found in most vascular beds where it most likely co-operates with tethering molecules, e.g. VCAM-1, in the recruitment of monocytes.

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“…Recently, fractalkine expressed in the interstitium was reported to be involved leukocyte influx including CD16 positive cells (25). Although, the intervention of fractalkine receptor, CX3CR1 showed the prevention of glomerular damage with the decrease in leukocyte infiltration (42), the blockade of fractalkine/its receptor may be beneficial to the prevention of interstitial damage as well as glomerular diseases. In addition, MCP-1, as anticipated, was involved in the interstitial nephritis (43).…”

Section: Interstitial Renal Damage and Chemokinesmentioning

confidence: 99%

Chemokines in renal diseases

Wada

Yokoyama

Matsushima

et al. 2001

International Immunopharmacology

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Prevention of crescentic glomerulonephritis by immunoneutralization of the fractalkine receptor CX3CR1: Rapid Communication

Abstract: Fractalkine plays a central role in leukocyte trafficking at the endothelium in the high-flow glomerular circuit and, in turn, implicates CX3CR1 as a prime drug target for therapeutic intervention of endothelium-related inflammatory diseases.

Cited by 180 publications

References 38 publications

Expression and Targeting of CX3CL1 (Fractalkine) in Renal Tubular Epithelial Cells

Expression and Targeting of CX3CL1 (Fractalkine) in Renal Tubular Epithelial Cells

Human fractalkine mediates leukocyte adhesion but not capture under physiological shear conditions; a mechanism for selective monocyte recruitment

Chemokines in renal diseases

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