Received November 8, 2007
Accepted on January 9, 2008

BASIC RESEARCH

CXCL9, but not CXCL10, Promotes CXCR3-Dependent Immune-Mediated Kidney Disease

Julia Menke ^*, Geraldine C. Zeller ^*, Eriya Kikawada ^*, Terry K. Means , Xiao R. Huang , Han Y. Lan , Bao Lu , Joshua Farber ^||, Andrew D. Luster , and Vicki R. Kelley ^*1

*Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women’s Hospital, Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, and Perlmutter Laboratory, Children’s Hospital and Harvard Medical School, Boston, Massachusetts; Department of Medicine, University of Hong Li Ka Shing Facility of Medicine, Hong Kong, China; and ||Inflammation Biology Section, Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Disease, National Institute of Child Health and Human Development, National Institute of Health, Bethesda, Maryland

¹ To whom correspondence should be addressed. E-mail: vkelley{at}rics.bwh.harvard.edu.

	Abstract

Chemokines are instrumental in macrophage- and T cell–dependent diseases. The chemokine CCL2 promotes kidney disease in two models of immune-mediated nephritis (MRL-Fas^lpr mice and the nephrotoxic serum nephritis model), but evidence suggests that multiple chemokines are involved. For identification of additional therapeutic targets for immune-mediated nephritis, chemokine ligands and receptors in CCL2^-/- and wild-type (WT) MRL-Fas^lpr kidneys were profiled. The focus was on intrarenal chemokine ligand/receptor pairs that were highly upregulated downstream of CCL2; the chemokine CXCL10 and its cognate receptor, CXCR3, stood out as potential therapeutic targets. However, renal disease was not suppressed in CXCL10^-/- MRL-Fas^lpr mice, and CXCL10^-/- C57BL/6 mice were not protected from nephrotoxic serum nephritis compared with WT mice. Because CXCR3 engages with the ligand CXCL9, CXCR3^-/-, CXCL9^-/-, and CXCL10^-/- B6 mice were compared with WT mice with nephrotoxic serum nephritis. Kidney disease, measured by loss of renal function and histopathology, was suppressed in both CXCR3^-/- and CXCL9^-/- mice but not in CXCL10^-/- mice. With nephrotoxic serum nephritis, CXCR3^-/- and CXCL9^-/- mice had fewer intrarenal activated T cells and activated macrophages. Both IgG glomerular deposits and antigen-specific IgG in serum were reduced in these mice, suggesting that although CXCR3 and CXCL9 initiate nephritis through cell-mediated events, renal inflammation may be sustained by their regulation of IgG. It is concluded that specific blockade of CXCL9 or CXCR3 may be a potential therapeutic target for human immune-mediated kidney diseases.