Chemokine receptor CXCR3 mediates T cell recruitment and tissue injury in nephrotoxic nephritis in mice.
The chemokine receptor CXCR3 is highly expressed on Th1 polarized T cells and has been predicted to play an important role in T cell recruitment and immune response in a number of inflammatory and autoimmune diseases. For testing whether CXCR3 plays a role in renal inflammation, CXCR3-deficient mice were generated and nephrotoxic nephritis was induced in C57BL/6 CXCR3(-/-) and C57BL/6 wild-type mice. Induction of the nephrotoxic nephritis leads to an increased renal mRNA expression of IP-10/CXCL10 (8.6-fold), Mig/CXCL9 (2.3-fold), and I-TAC/CXCL11 (4.9-fold) during the autologous phase at days 7 and 14. This increased chemokine expression was paralleled by the renal infiltration of T cells, followed by renal tissue injury, albuminuria, and loss of renal function. Compared with wild-type mice, CXCR3-deficient mice had significantly reduced renal T cell infiltrates. Moreover, CXCR3(-/-) mice developed less severe nephritis, with significantly lower albuminuria, better renal function, and a reduced frequency of glomerular crescent formation. Nephritic wild-type and CXCR3(-/-) mice both elicited an efficient systemic nephritogenic immune response in terms of antigen-specific IgG production and IFN-gamma expression by splenocytes in response to the nephritogenic antigen. These findings indicate that the ameliorated nephritis in CXCR3-deficient mice is due to impaired renal trafficking of effector T cells rather than their inability to mount an efficient humoral or cellular immune response. The neutralization of CXCR3 might be a promising therapeutic strategy for Th1-dependent inflammatory renal disease.
Panzer
Ulf
U
Medizinische Klinik III, Zentrum für Innere Medizin, University of Hamburg, Martinistrasse 52, Hamburg, Germany.
Steinmetz
Oliver M
OM
Paust
Hans-Joachim
HJ
Meyer-Schwesinger
Catherine
C
Peters
Anett
A
Turner
Jan-Eric
JE
Zahner
Gunther
G
Heymann
Felix
F
Kurts
Christian
C
Hopfer
Helmut
H
Helmchen
Udo
U
Haag
Friedrich
F
Schneider
André
A
Stahl
Rolf A K
RA
D000818:Animals; D051379:Mice; D008810:Mice, Inbred C57BL; D009393:Nephritis / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*
C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine