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Selective Binding and Presentation of CCL5 by Discrete Tissue Microenvironments during Renal Inflammation

Stephan Segerer^*, Roghieh Djafarzadeh^*, Hermann-Josef Gröne, Christian Weingart^*, Dontscho Kerjaschki, Christian Weber, Andreas J. Kungl^||, Heinz Regele, Amanda E.I. Proudfoot^¶ and Peter J. Nelson^*

^* Medizinische Poliklinik-Innenstadt, University of Munich, Germany; Department of Cellular and Molecular Pathology, German Cancer Research Center, Heidelberg, Germany; Clinical Institute of Pathology, University of Vienna, Vienna, Austria; Institute for Molecular Cardiovascular Research, University of Aachen, Aachen, Germany; ^|| University of Graz, Graz, Austria; and ^¶ Serono Pharmaceutical Research Institute, Geneva, Switzerland

Address correspondence to: Dr. Stephan Segerer, Medizinische Poliklinik-Innenstadt, University of Munich, Pettenkoferstrasse 8a, 80336 Munich, Germany. Phone: +49-89-5160-3565; Fax: +49-89-5160-4439; E-mail: stephan.segerer{at}lrz.uni-muenchen.de

Received for publication August 9, 2006. Accepted for publication March 29, 2007.

T cells are differentially recruited to the tubulointerstitium during renal inflammation. The selective presentation of chemokines by surface structures may in part underlie this phenomenon. In an attempt to better characterize the presentation of chemokines by tissue environments an exemplary chemokine with a well-defined structure was selected, and a binding assay for the protein on fixed archival tissue sections was developed. This article describes the selective binding of the chemokine CCL5 to renal structures. CCL5 was shown to bind to endothelial regions, interstitial extracellular matrix, tubular epithelial cells, and tubular basement membranes but rarely to glomerular structures in well-preserved kidneys. In contrast, binding of CCL5 to glomerular components was seen in renal biopsies with acute allograft glomerulitis (in which T cells accumulate in glomeruli). The N terminus mediates receptor binding, whereas two clusters of basic amino acid residues (⁴⁴RKNR⁴⁷ and ⁵⁵KKWVR⁵⁹) are involved in the presentation of CCL5 by extracellular structures. Mutation of either loop abrogated CCL5 binding to tissue sections. Variations of the N terminus and a mutation that prevents higher order oligomerization did not change the binding pattern. The data suggest that renal compartments differ in their capacity to present chemokines, which may help explain the differential recruitment of leukocytes during allograft injury. Both clusters of basic residues in CCL5 are necessary for sufficient binding of CCL5 to tissue sections.

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J. Am. Soc. Nephrol. 2007 18: 1617-1618. [Full Text] [PDF]

Copyright © 2008 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673