title: CCR1 inhibition ameliorates the progression of lupus nephritis in NZB/W mice.
abstract: Systemic lupus erythematosus is a chronic inflammatory autoimmune disease, the development of which is characterized by a progressive loss of renal function. Such dysfunction is associated with leukocyte infiltration in the glomerular and tubulointerstitial compartments in both human and experimental lupus nephritis. In this study, we investigated the role of the Ccr1 chemokine receptor in this infiltration process during the progression of nephritis in the lupus-prone New Zealand Black/New Zealand White (NZB/W) mouse model. We found that peripheral T cells, mononuclear phagocytes, and neutrophils, but not B cells, from nephritic NZB/W mice were more responsive to Ccr1 ligands than the leukocytes from younger prenephritic NZB/W mice. Short-term treatment of nephritic NZB/W mice with the orally available Ccr1 antagonist BL5923 decreased renal infiltration by T cells and macrophages. Longer Ccr1 blockade decreased kidney accumulation of effector/memory CD4(+) T cells, Ly6C(+) monocytes, and both M1 and M2 macrophages; reduced tubulointerstitial and glomerular injuries; delayed fatal proteinuria; and prolonged animal lifespan. In contrast, renal humoral immunity was unaffected in BL5923-treated mice, which reflected the unchanged numbers of infiltrated B cells in the kidneys. Altogether, these findings define a pivotal role for Ccr1 in the recruitment of T and mononuclear phagocyte cells to inflamed kidneys of NZB/W mice, which in turn contribute to the progression of renal injury.
authors.affiliation: Université Paris-Sud, Laboratoire "Cytokines, Chimiokines et Immunopathologie," Unité Mixte de Recherche S996, 92140 Clamart, France;
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bignon
authors.forename: Françoise
authors.initials: F
authors.lastname: Gaudin
authors.forename: Patrice
authors.initials: P
authors.lastname: Hémon
authors.forename: Hugo
authors.initials: H
authors.lastname: Tharinger
authors.forename: Katia
authors.initials: K
authors.lastname: Mayol
authors.forename: Thierry
authors.initials: T
authors.lastname: Walzer
authors.forename: Pius
authors.initials: P
authors.lastname: Loetscher
authors.forename: Michel
authors.initials: M
authors.lastname: Peuchmaur
authors.forename: Dominique
authors.initials: D
authors.lastname: Berrebi
authors.forename: Karl
authors.initials: K
authors.lastname: Balabanian
mesh_terms: D000367:Age Factors; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D054405:Chemokine CCL3 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002634:Chemotaxis, Leukocyte; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008024:Ligands; D008181:Lupus Nephritis / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008814:Mice, Inbred NZB; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D020556:Neutrophil Infiltration / Q000187:drug effects; D012333:RNA, Messenger / Q000096:biosynthesis; D011897:Random Allocation; D054389:Receptors, CCR1 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013163:Splenomegaly / Q000209:etiology / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism / Q000473:pathology
chemical_list: C496534:Ccl3 protein, mouse; C503460:Ccl5 protein, mouse; C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D018946:Chemokine CCL5; D008024:Ligands; D012333:RNA, Messenger; D054389:Receptors, CCR1