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CXCR3 Mediates Renal Th1 and Th17 Immune Response in Murine Lupus Nephritis¹

Oliver M. Steinmetz^2,*, Jan-Eric Turner^2,*, Hans-Joachim Paust^*, Matthias Lindner^*, Anett Peters^*, Kirstin Heiss, Joachim Velden, Helmut Hopfer, Susanne Fehr^¶, Thorsten Krieger, Catherine Meyer-Schwesinger^*, Tobias N. Meyer^*, Udo Helmchen, Hans-Willi Mittrücker, Rolf A. K. Stahl^* and Ulf Panzer^3,*

^* III. Medizinische Klinik, Institut für Immunologie, and Institut für Pathologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany; Institut für Pathologie, Universitätsspital Basel, Basel, Switzerland; and ^¶ Servicegruppe Morphologie, Zentrum für Molekulare Neurobiologie Hamburg, Hamburg, Germany

Infiltration of T cells into the kidney is a typical feature of human and experimental lupus nephritis that contributes to renal tissue injury. The chemokine receptor CXCR3 is highly expressed on Th1 cells and is supposed to be crucial for their trafficking into inflamed tissues. In this study, we explored the functional role of CXCR3 using the MRL/MpJ-Fas^lpr (MRL/lpr) mouse model of systemic lupus erythematosus that closely resembles the human disease. CXCR3^–/– mice were generated and backcrossed into the MRL/lpr background. Analysis of 20-wk-old CXCR3^–/– MRL/lpr mice showed amelioration of nephritis with reduced glomerular tissue damage and decreased albuminuria and T cell recruitment. Most importantly, not only the numbers of renal IFN--producing Th1 cells, but also of IL-17-producing Th17 cells were significantly reduced. Unlike in inflamed kidneys, there was no reduction in the numbers of IFN-- or IL-17-producing T cells in spleens, lymph nodes, or the small intestine of MRL/lpr CXCR3^–/– mice. This observation suggests impaired trafficking of effector T cells to injured target organs, rather than the inability of CXCR3^–/– mice to mount efficient Th1 and Th17 immune responses. These findings show a crucial role for CXCR3 in the development of experimental lupus nephritis by directing pathogenic effector T cells into the kidney. For the first time, we demonstrate a beneficial effect of CXCR3 deficiency through attenuation of both the Th1 and the newly defined Th17 immune response. Our data therefore identify the chemokine receptor CXCR3 as a promising therapeutic target in lupus nephritis.

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, STE 1822/1-1, and KFO 228 Project 1).

² O.M.S. and J.-E.T. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Ulf Panzer, Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Martinistrasse 52, 20246 Hamburg, Germany. E-mail address: panzer{at}uke.uni-hamburg.de

⁴ Abbreviations used in this paper: SLE, systemic lupus erythematosus; BUN, blood urea nitrogen; DN, double negative; IP10, IFN--inducible protein 10; Mig, monokine induced by IFN-; NTN, nephrotoxic serum nephritis; PAS, periodic acid-Schiff; SNP, single nucleotide polymorphism; ITAC, IFN-inducible T cell chemoattractant.

⁵ The online version of this article contains supplemental material.