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CCR5 Deficiency Aggravates Crescentic Glomerulonephritis in Mice¹

Jan-Eric Turner^*, Hans-Joachim Paust^*, Oliver M. Steinmetz^*, Anett Peters^*, Catherine Meyer-Schwesinger^*, Felix Heymann, Udo Helmchen, Susanne Fehr, Richard Horuk^¶, Ulrich Wenzel^*, Christian Kurts, Hans-Willi Mittrücker^||, Rolf A. K. Stahl^* and Ulf Panzer^2,*

^* III. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Institute for Molecular Medicine and Experimental Immunology, Universitätsklinikum Bonn, Bonn, Germany; Institut für Pathologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Servicegruppe Morphologie, Zentrum für Molekulare Neurobiologie, Hamburg, Germany; ^¶ Department of Immunology, Berlex Biosciences, Richmond, CA 94804; and ^|| Institut für Immunologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany

The chemokine receptor CCR5 is predominantly expressed on monocytes and Th1-polarized T cells, and plays an important role in T cell and monocyte recruitment in inflammatory diseases. To investigate the functional role of CCR5 in renal inflammation, we induced a T cell-dependent model of glomerulonephritis (nephrotoxic serum nephritis) in CCR5^–/– mice. Induction of nephritis in wild-type mice resulted in up-regulation of renal mRNA expression of the three CCR5 chemokine ligands, CCL5 (15-fold), CCL3 (4.9-fold), and CCL4 (3.4-fold), in the autologous phase of the disease at day 10. The up-regulated chemokine expression was paralleled by infiltration of monocytes and T cells, followed by renal tissue injury, albuminuria, and loss of renal function. Nephritic CCR5^–/– mice showed a 3- to 4-fold increased renal expression of CCL5 (61.6-fold vs controls) and CCL3 (14.1-fold vs controls), but not of CCL4, in comparison with nephritic wild-type mice, which was accompanied by augmented renal T cell and monocyte recruitment and increased lethality due to uremia. Furthermore, CCR5^–/– mice showed an increased renal Th1 response, whereas their systemic humoral and cellular immune responses were unaltered. Because the CCR5 ligands CCL5 and CCL3 also act via CCR1, we investigated the effects of the pharmacological CCR1 antagonist BX471. CCR1 blockade in CCR5^–/– mice significantly reduced renal chemokine expression, T cell infiltration, and glomerular crescent formation, indicating that increased renal leukocyte recruitment and consecutive tissue damage in nephritic CCR5^–/– mice depended on functional CCR1. In conclusion, this study shows that CCR5 deficiency aggravates glomerulonephritis via enhanced CCL3/CCL5-CCR1-driven renal T cell recruitment.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from the Deutsche Forschungsgemeinschaft (PA 754/6-3) and by a fellowship of the German National Academic Foundation to F.H.

² Address correspondence and reprint requests to Dr. Ulf Panzer, Universitätsklinikum Hamburg-Eppendorf III. Medizinische Klinik, Martinistr. 52, 20246 Hamburg Germany. E-mail address: panzer{at}uke.uni-hamburg.de

³ Abbreviations used in this paper: NTN, nephrotoxic serum nephritis; BUN, blood urea nitrogen; gcs, glomerular cross-section; hpf, high power field; PAS, Periodic acid Schiff; WT, wild type.