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CXCR4/CXCL12 Hyperexpression Plays a Pivotal Role in the Pathogenesis of Lupus¹

Andrew Wang^*,, Anna-Marie Fairhurst, Katalin Tus, Srividya Subramanian, Yang Liu^*, Fangming Lin, Peter Igarashi^*, Xin J. Zhou, Frederic Batteux^¶, Donald Wong^||, Edward K. Wakeland^2, and Chandra Mohan^2,*,

^* Department of Internal Medicine, Department of Immunology, Department of Pediatrics, and Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390; ^¶ Laboratoire d’Immunologie, EA1833, Faculté de Médecine, Université Paris-Descartes, Paris, France; and ^|| Chemokine Therapeutics, Vancouver, British Columbia, Canada

Among various surface molecules screened, CXCR4 was significantly up-regulated on monocytes, neutrophils, B cell subsets, and plasma cells in multiple murine models of lupus with active nephritis, including B6.Sle1Yaa, BXSB, and MRL.lpr. TLR-mediated signaling and inflammatory cytokines accounted in part for this increase. Increased CXCR4 expression was associated with functional consequences, including increased migration and enhanced B cell survival. Simultaneously, the ligand for CXCR4, CXCL12, was significantly up-regulated in the nephritic kidneys. Treatment with a peptide antagonist of CXCR4 prolonged survival and reduced serum autoantibodies, splenomegaly, intrarenal leukocyte trafficking, and end organ disease in a murine model of lupus. These findings underscore the pathogenic role of CXCR4/CXCL12 in lymphoproliferative lupus and lupus nephritis and highlight this axis as a promising therapeutic target in this disease.

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 National Institutes of Health (NIH) Grant P01 AI-039824, the Arthritis Foundation, the O'Brien Kidney Research Center (NIH Grant P30 DK079328), and a NIH training grant (to A.W.).

² Address correspondence and reprint requests Dr. Chandra Mohan and Dr. Edward K. Wakeland, Department of Internal Medicine/Rheumatology, University of Texas Southwestern Medical Center, Mail Code 8884, Y8.204, 5323 Harry Hines Boulevard, Dallas, TX 75390. E-mail addresses: Chandra.mohan{at}utsouthwestern.edu and Edward.wakeland{at}utsouthwestern.edu

³ Abbreviations used in this paper: MFI, mean fluorescent intensity; ANA, antinuclear autoantibody.

⁴ The online version of this article contains supplemental material.

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				A.-M. Fairhurst, C. Xie, Y. Fu, A. Wang, C. Boudreaux, X. J. Zhou, R. Cibotti, A. Coyle, J. E. Connolly, E. K. Wakeland, et al. Type I Interferons Produced by Resident Renal Cells May Promote End-Organ Disease in Autoantibody-Mediated Glomerulonephritis J. Immunol., November 15, 2009; 183(10): 6831 - 6838. [Abstract] [Full Text] [PDF]