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

• Published in: Journal of the American Society of Nephrology Vol. 19; no. 6; pp. 1177 - 1189
• Main Authors: MENKE, Julia, ZELLER, Geraldine C, KIKAWADA, Eriya, MEANS, Terry K, HUANG, Xiao R, LAN, Han Y, BAO LU, FARBER, Joshua, LUSTER, Andrew D, KELLEY, Vicki R
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01.06.2008; American Society of Nephrology
• Subjects: Animals; Basic Research; Biological and medical sciences; Chemokine CXCL10 - physiology; Chemokine CXCL9 - physiology; Medical sciences; Mice; Nephritis - etiology; Nephritis - immunology; Nephrology. Urinary tract diseases; Receptors, CXCR3 - physiology; Kidney disease; Nephrology; Urinary system disease; Nephropathy; CXCL9 chemokine; CXCL10 chemokine; Chemokine receptor; CXC chemokine; Urology; Interferon gamma inducible protein 10; CXCR3 chemokine receptor
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/ASN.2007111179

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