title: CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease.
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
authors.affiliation: Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, MA, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Menke
authors.forename: Geraldine C
authors.initials: GC
authors.lastname: Zeller
authors.forename: Eriya
authors.initials: E
authors.lastname: Kikawada
authors.forename: Terry K
authors.initials: TK
authors.lastname: Means
authors.forename: Xiao R
authors.initials: XR
authors.lastname: Huang
authors.forename: Han Y
authors.initials: HY
authors.lastname: Lan
authors.forename: Bao
authors.initials: B
authors.lastname: Lu
authors.forename: Joshua
authors.initials: J
authors.lastname: Farber
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
authors.forename: Vicki R
authors.initials: VR
authors.lastname: Kelley
mesh_terms: D000818:Animals; D054357:Chemokine CXCL10 / Q000502:physiology*; D054370:Chemokine CXCL9 / Q000502:physiology*; D051379:Mice; D009393:Nephritis / Q000209:etiology / Q000276:immunology*; D054367:Receptors, CXCR3 / Q000502:physiology*
chemical_list: C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D054367:Receptors, CXCR3