title: Chemokine receptor CXCR3 mediates T cell recruitment and tissue injury in nephrotoxic nephritis in mice.
abstract: 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.
authors.affiliation: Medizinische Klinik III, Zentrum für Innere Medizin, University of Hamburg, Martinistrasse 52, Hamburg, Germany.
authors.forename: Ulf
authors.initials: U
authors.lastname: Panzer
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Steinmetz
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Paust
authors.forename: Catherine
authors.initials: C
authors.lastname: Meyer-Schwesinger
authors.forename: Anett
authors.initials: A
authors.lastname: Peters
authors.forename: Jan-Eric
authors.initials: JE
authors.lastname: Turner
authors.forename: Gunther
authors.initials: G
authors.lastname: Zahner
authors.forename: Felix
authors.initials: F
authors.lastname: Heymann
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.forename: Helmut
authors.initials: H
authors.lastname: Hopfer
authors.forename: Udo
authors.initials: U
authors.lastname: Helmchen
authors.forename: Friedrich
authors.initials: F
authors.lastname: Haag
authors.forename: André
authors.initials: A
authors.lastname: Schneider
authors.forename: Rolf A K
authors.initials: RA
authors.lastname: Stahl
mesh_terms: 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*
chemical_list: C515188:Cxcr3 protein, mouse; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine