CXCL9, but not CXCL10, promotes CXCR3-dependent immune-mediated kidney disease.
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
Menke
Julia
J
Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women's Hospital, Boston, MA, USA.
Zeller
Geraldine C
GC
Kikawada
Eriya
E
Means
Terry K
TK
Huang
Xiao R
XR
Lan
Han Y
HY
Lu
Bao
B
Farber
Joshua
J
Luster
Andrew D
AD
Kelley
Vicki R
VR
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*
C515187:CXCR3 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D054367:Receptors, CXCR3