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Circulating CSF-1 Promotes Monocyte and Macrophage Phenotypes that Enhance Lupus Nephritis

Julia Menke^*, Whitney A. Rabacal^*, Katelyn T. Byrne^*, Yasunori Iwata^*, Melvin M. Schwartz, E. Richard Stanley, Andreas Schwarting and Vicki R. Kelley^*

^* Laboratory of Molecular Autoimmune Disease, Renal Division, Brigham and Women’s Hospital, Boston, Massachusetts;
Department of Pathology, Rush University Medical Center, Chicago, Illinois;
Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York; and
Department of Nephrology and Rheumatology, Johannes-Gutenberg University Mainz, Germany

Correspondence: Dr. Vicki Rubin Kelley, Harvard Institutes of Medicine, 4 Black Fan Circle, Boston, MA 02115. Phone: 617-525-5915; Fax: 617-525-5830; E-mail: vkelley{at}rics.bwh.harvard.edu.

Received for publication May 12, 2009. Accepted for publication September 17, 2009.

Macrophages mediate kidney disease and are prominent in a mouse model (MRL-Fas^lpr) of lupus nephritis. Colony stimulating factor-1 (CSF-1) is the primary growth factor for macrophages, and CSF-1 deficiency protects MRL-Fas^lpr mice from kidney disease and systemic illness. Whether this renoprotection derives from a reduction of macrophages and whether systemic CSF-1, as opposed to intrarenal CSF-1, promotes macrophage-dependent lupus nephritis remain unclear. Here, we found that increasing systemic CSF-1 hastened the onset of lupus nephritis in MRL-Fas^lpr mice. Using mutant MRL-Fas^lpr strains that express high, moderate, or no systemic CSF-1, we detected a much higher tempo of kidney disease in mice with the highest level of CSF-1. Furthermore, we uncovered a multistep CSF-1-dependent systemic mechanism central to lupus nephritis. CSF-1 heightened monocyte proliferation in the bone marrow (SSC^lowCD11b⁺), and these monocytes subsequently seeded the circulation. Systemic CSF-1 skewed the frequency of monocytes toward "inflammatory" (SSC^lowCD11b⁺Ly6C^high) and activated populations that homed to sites of inflammation, resulting in a more rapid accumulation of intrarenal macrophages (CD11b⁺CSF-1R⁺ or CD68⁺) that induced apoptosis of tubular epithelial cells, damaging the kidney. In humans, we found increased levels of CSF-1 in the serum, urine, and kidneys of patients with lupus compared with healthy controls. Furthermore, serum and urine CSF-1 levels correlated with lupus activity, and intrarenal CSF-1 expression correlated with the histopathology activity index of lupus nephritis. Taken together, circulating CSF-1 is a potential therapeutic target for lupus nephritis.

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J. Am. Soc. Nephrol. 2009 20: A10. [Full Text] [PDF]

Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673