title: Macrophage depletion ameliorates nephritis induced by pathogenic antibodies.
abstract: Kidney involvement affects 40-60% of patients with lupus, and is responsible for significant morbidity and mortality. Using depletion approaches, several studies have suggested that macrophages may play a key role in the pathogenesis of lupus nephritis. However, "off target" effects of macrophage depletion, such as altered hematopoiesis or enhanced autoantibody production, impeded the determination of a conclusive relationship. In this study, we investigated the role of macrophages in mice receiving rabbit anti-glomerular antibodies, or nephrotoxic serum (NTS), an experimental model which closely mimics the immune complex mediated disease seen in murine and human lupus nephritis. GW2580, a selective inhibitor of the colony stimulating factor-1 (CSF-1) receptor kinase, was used for macrophage depletion. We found that GW2580-treated, NTS challenged mice did not develop the increased levels of proteinuria, serum creatinine, and BUN seen in control-treated, NTS challenged mice. NTS challenged mice exhibited significantly increased kidney expression of inflammatory cytokines including RANTES, IP-10, VCAM-1 and iNOS, whereas GW2580-treated mice were protected from the robust expression of these inflammatory cytokines that are associated with lupus nephritis. Quantification of macrophage related gene expression, flow cytometry analysis of kidney single cell suspensions, and immunofluorescence staining confirmed the depletion of macrophages in GW2580-treated mice, specifically within renal glomeruli. Our results strongly implicate a specific and necessary role for macrophages in the development of immune glomerulonephritis mediated by pathogenic antibodies, and support the development of macrophage targeting approaches for the treatment of lupus nephritis.
authors.affiliation: The Department of Microbiology and Immunology and the Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Chalmers
authors.affiliation: The Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Violeta
authors.initials: V
authors.lastname: Chitu
authors.affiliation: Department of Pathology, Columbia-Presbyterian Medical Center, New York, NY 10032, USA.
authors.forename: Leal C
authors.initials: LC
authors.lastname: Herlitz
authors.affiliation: The Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Ranjit
authors.initials: R
authors.lastname: Sahu
authors.affiliation: The Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: E Richard
authors.initials: ER
authors.lastname: Stanley
authors.affiliation: The Department of Microbiology and Immunology and the Division of Rheumatology, Albert Einstein College of Medicine, Bronx, NY 10461, USA. Electronic address: chaim.putterman@einstein.yu.edu.
authors.forename: Chaim
authors.initials: C
authors.lastname: Putterman
mesh_terms: D000818:Animals; D000840:Anisoles / Q000276:immunology* / Q000494:pharmacology; D000906:Antibodies / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D005921:Glomerulonephritis / Q000276:immunology / Q000517:prevention & control; D024243:HMGB1 Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007678:Kidney Glomerulus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology* / Q000517:prevention & control; D008264:Macrophages / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D011507:Proteinuria / Q000276:immunology / Q000517:prevention & control; D011743:Pyrimidines / Q000276:immunology* / Q000494:pharmacology; D011817:Rabbits; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; D000906:Antibodies; D024243:HMGB1 Protein; D007074:Immunoglobulin G; D011743:Pyrimidines; D020780:Matrix Metalloproteinase 9
keywords: Lupus nephritis; Macrophages; Nephrotoxic serum nephritis (NTS); SLE