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  • of October 16, 2018.This information is current as

    of Lupus Nephritis in NZB/W MiceCCR1 Inhibition Ameliorates the Progression

    Michel Peuchmaur, Dominique Berrebi and Karl BalabanianTharinger, Katia Mayol, Thierry Walzer, Pius Loetscher, Alexandre Bignon, Franoise Gaudin, Patrice Hmon, Hugo

    http://www.jimmunol.org/content/192/3/886doi: 10.4049/jimmunol.1300123December 2013;

    2014; 192:886-896; Prepublished online 23J Immunol

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    3.DC1http://www.jimmunol.org/content/suppl/2013/12/24/jimmunol.130012

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  • The Journal of Immunology

    CCR1 Inhibition Ameliorates the Progression of LupusNephritis in NZB/W Mice

    Alexandre Bignon,*, Francoise Gaudin,*, Patrice Hemon,*, Hugo Tharinger,

    Katia Mayol,x Thierry Walzer,x Pius Loetscher,{ Michel Peuchmaur,,#

    Dominique Berrebi,*,,,# and Karl Balabanian*,

    Systemic lupus erythematosus is a chronic inflammatory autoimmune disease, the development of which is characterized by a pro-

    gressive 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 re-

    ceptor 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/Wmice were more responsive to Ccr1 ligands than the leukocytes from younger prenephritic NZB/Wmice. Short-term treat-

    ment of nephritic NZB/W mice with the orally available Ccr1 antagonist BL5923 decreased renal infiltration by T cells and macro-

    phages. 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 life-

    span. 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. The Journal of

    Immunology, 2014, 192: 886896.

    Systemic lupus erythematosus (SLE) is a chronic, inflamma-tory autoimmune disease characterized by the productionof autoantibodies against nuclear Ags; immune complex

    deposition in multiple organs, including the kidney; complement

    activation; leukocyte infiltration; and tissue damage (13). Leu-kocyte infiltration features in both human and experimental lupusnephritis and is strikingly associated with a progressive loss ofrenal function (4, 5). This infiltration includes T cells, B cells,neutrophils, and mononuclear phagocytes, and involves the glo-merular as well as the tubulointerstitial compartments of the kidney(6, 7). Infiltrating leukocytes constitute a source of inflammatoryand profibrotic mediators (e.g., cytokines, chemokines, extracel-lular matrix proteins), which contribute to the proliferation anddifferentiation of resident kidney cells and to matrix depositionleading to renal injury (710). Thus, preventing or reducing leu-kocyte recruitment into inflamed kidneys should inhibit the pro-gression of lupus nephritis.Chemokines and their seven-transmembrane G-proteincoupled

    receptors are critical mediators in the inflammatory process andthus represent attractive therapeutic targets (11, 12). Many studiesrevealed that locally produced inflammatory chemokines (e.g.,Ccl2 to Ccl5, Cxcl10 to Cxcl13) govern the complex multistepprocess leading to renal leukocyte infiltration and injury in dif-ferent mouse models of nephropathy (1319). In New ZealandBlack/New Zealand White (NZB/W) mice, which spontaneouslydevelop a severe autoimmune disease and more closely mimic thehuman SLE condition compared with other rodent models (20),we previously reported that splenic T, B, and myeloid cells fromnephritic mice migrated into noninflamed syngeneic kidneys (19).This process was enhanced if the recipient kidneys were chroni-cally inflamed, indicating that circulating leukocytes and thekidney both contribute to the inflammation in lupus nephritisthrough a self-maintenance mechanism. Elevated renal expressionof two Ccr1 chemokine receptor ligands: Ccl3 and Ccl5, in as-sociation with mononuclear phagocytes and T cell infiltration havebeen reported in NZB/W mice, as well as in other models of SLEand in human lupus nephritis (16, 19, 21). Thus, Ccr1 may me-diate the coordinated recruitment of inflammatory leukocytes to

    *Universite Paris-Sud, Laboratoire Cytokines, Chimiokines et Immunopathologie,Unite Mixte de Recherche S996, 92140 Clamart, France; INSERM, LaboratoiredExcellence en Recherche sur le Medicament et lInnovation Therapeutique, 92140Clamart, France; Institut Paris-Sud dInnovation Therapeutique/Institut Federatif deRecherche 141, 92290 Chatenay-Malabry, France; xCentre International de Rechercheen Infectiologie, INSERM U1111, Ecole Normale Superieure, Universite Lyon 1,Centre National de la Recherche Scientifique, Unite Mixte de Recherche 5308,69365 Lyon Cedex 07, France; {Novartis Institutes for BioMedical Research, NovartisPharma AG, CH-4056 Basel, Switzerland; Service dAnatomie et de Cytologie Path-ologique, Unite Propre de Recherche de lEnseignement Superieur Associe 1320,Hopital Robert Debre, 75019 Paris, France; and #Universite Denis Diderot, UniversiteParis 7, 75013 Paris France

    Received for publication January 14, 2013. Accepted for publication November 19,2013.

    This work was supported by the Assistance Publique-Hopitaux de Paris (Grant 07018)and the Agence Nationale de la Recherche (Grant 2010 JCJC 1104 01). A.B., F.G.,and K.B. are members of the Laboratory of Excellence in Research on Medica-tion and Innovative Therapeutics, supported by a grant from the Agence Nationalede la Recherche (ANR-10-LABX-33) under the program Investissements dAvenirANR-11-IDEX-0003-01. A.B. was the recipient of a fellowship from the FrenchMinistry and from the Fondation pour la Recherche Medicale (FDT20130928127).

    A.B. and K.B. conceived and designed the experiments. A.B., F.G., P.H., H.T., M.P,D.B., and K.B. performed the experiments. A.B., M.P., D.B., and K.B. analyzed thedata. K.M., T.W., and P.L. contributed to reagents/materials/analysis tools. A.B., D.B.,and K.B. wrote the paper. K.B. provided funding. A.B., F.G., P.H., H.T., K.M., T.W.,P.L., M.P., D.B., and K.B. read and approved the final manuscript.

    Address correspondence and reprint requests to Dr. Karl Balabanian. INSERM, UniteMixte de Recherche S996, Universite Paris-Sud, Laboratoire dExcellence enRecherche sur le Medicament et lInnovation Therapeutique, 32 Rue des Carnets,92140 Clamart, France. E-mail address: karl.balabanian@u-psud.fr

    The online version of this article contains supplemental material.

    Abbreviations used in this article: CMTMR, 5-(6)-(((4-chloromethyl) benzoyl) amino)tetramethylrhodamine; IHC, immunohistochemistry; NZB/W, New Zealand Black/NewZealand White; SLE, systemic lupus erythematosus; Treg, regulatory T cell.

    Copyright 2014 by TheAmericanAssociation of Immunologists, Inc. 0022-1767/14/$16.00

    www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300123

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  • sites of renal injury, resulting in tubular and/or glomerular lesionsand tissue fibrosis. Indeed, accumulation of CCR1-positive mac-rophages and lymphocytes is found mainly in interstitial lesions ofrenal biopsies from SLE patients (22), and Ccr1 on myeloid cellsand some T cell subsets is thought to guide t

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