CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

被引:33
作者
Bignon, Alexandre [1 ,2 ]
Gaudin, Francoise [1 ,2 ]
Hemon, Patrice [1 ,2 ]
Tharinger, Hugo [3 ]
Mayol, Katia
Walzer, Thierry [4 ]
Loetscher, Pius [5 ]
Peuchmaur, Michel [6 ,7 ]
Berrebi, Dominique [1 ,2 ,6 ,7 ]
Balabanian, Karl [1 ,2 ]
机构
[1] Univ Paris 11, Lab Cytokines Chimiokines & Immunopathol, Unite Mixte Rech S996, F-92140 Clamart, France
[2] INSERM, Lab Excellence Rech Med & Innovat Therapeut, F-92140 Clamart, France
[3] Inst Federatif Rech, Inst Paris Sud Innovat Therapeut, F-92290 Chatenay Malabry, France
[4] Univ Lyon 1, Ecole Normale Super, Ctr Int Rech Infectiol, INSERM,U1111,Unite Mixte Rech 5308,CNRS, F-69365 Lyon 07, France
[5] Novartis Pharma AG, Novartis Inst BioMed Res, CH-4056 Basel, Switzerland
[6] Hop Robert Debre, Unite Propre Rech Enseignement Super Associe, Serv Anat & Cytol Pathol, F-75019 Paris, France
[7] Univ Paris 07, Univ Denis Diderot, F-75013 Paris, France
关键词
CHEMOKINE RECEPTOR CCR1; INFLAMMATORY CELL INFILTRATION; MURINE LUPUS; INTERSTITIAL INFLAMMATION; LEUKOCYTE RECRUITMENT; GENE-EXPRESSION; RENAL FIBROSIS; T-LYMPHOCYTES; DISEASE; ERYTHEMATOSUS;
D O I
10.4049/jimmunol.1300123
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
收藏
页码:886 / 896
页数:11
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