title: Protective role for CCR5 in murine lupus nephritis.
abstract: Leukocyte infiltration is a characteristic feature of human and experimental lupus nephritis and is closely correlated with loss of renal function. The chemokine receptor CCR5 is expressed on monocyte and T cell subsets and is thought to play an important role in recruiting these cells into inflamed organs. To investigate the functional role of CCR5 in lupus nephritis, CCR5-deficient mice were backcrossed onto the lupus-prone MRL-Fas(lpr) (MRL/lpr) genetic background. Unexpectedly, CCR5(-/-) MRL/lpr mice developed an aggravated course of lupus nephritis in terms of glomerular tissue injury and albuminuria. Deterioration of the nephritis was associated with an overall increase in mononuclear cell infiltration into the kidney, whereas renal leukocyte subtype balance, systemic T cell response, and autoantibody formation were unaffected by CCR5 deficiency. Renal and systemic protein levels of the CCR5 ligand CCL3, which can also attract leukocytes via its alternate receptor CCR1, were significantly increased in nephritic CCR5(-/-) MRL/lpr mice. Further studies revealed that the systemic increase in the CCR5/CCR1 ligand is also observed in nonimmune CCR5(-/-) C57BL/6 mice and that this increase was due to a reduced clearance, rather than an overproduction, of CCL3. Taken together, our data support the hypothesis that CCR5-dependent consumption of its own ligands may act as a negative feedback loop to restrain local chemokine levels within inflamed tissues, thereby limiting inflammatory cell influx.
authors.affiliation: Universitätsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Martinistrasse 52, Hamburg, Germany.
authors.forename: Jan-Eric
authors.initials: JE
authors.lastname: Turner
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Paust
authors.forename: Sabrina B
authors.initials: SB
authors.lastname: Bennstein
authors.forename: Phillip
authors.initials: P
authors.lastname: Bramke
authors.forename: Christian
authors.initials: C
authors.lastname: Krebs
authors.forename: Oliver M
authors.initials: OM
authors.lastname: Steinmetz
authors.forename: Joachim
authors.initials: J
authors.lastname: Velden
authors.forename: Friedrich
authors.initials: F
authors.lastname: Haag
authors.forename: Rolf A K
authors.initials: RA
authors.lastname: Stahl
authors.forename: Ulf
authors.initials: U
authors.lastname: Panzer
mesh_terms: D000818:Animals; D015551:Autoimmunity; D049109:Cell Proliferation; D002469:Cell Separation; D002478:Cells, Cultured; D018925:Chemokines / Q000378:metabolism; D004247:DNA / Q000235:genetics; D003713:Dendritic Cells / Q000502:physiology; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007668:Kidney / Q000166:cytology; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007962:Leukocytes / Q000502:physiology; D008181:Lupus Nephritis / Q000235:genetics* / Q000503:physiopathology*; D008208:Lymphatic System / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009395:Nephritis, Interstitial / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D019713:Receptors, CCR5 / Q000235:genetics* / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000378:metabolism
chemical_list: D018925:Chemokines; D019713:Receptors, CCR5; D004247:DNA