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, Vicki Rubin Kelley

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60 Scopus citations

Abstract

Macrophages mediate kidney disease and are prominent in a mouse model (MRL-Faslpr) of lupus nephritis. Colony stimulating factor-1 (CSF-1) is the primary growth factor for macrophages, and CSF-1 deficiency protects MRL-Faslpr 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-Faslpr mice. Using mutant MRL-Faslpr 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 (SSClowCD11b+), and these monocytes subsequently seeded the circulation. Systemic CSF-1 skewed the frequency of monocytes toward "inflammatory" (SSClowCD11b +Ly6Chigh) 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.

Original languageEnglish (US)
Pages (from-to)2581-2592
Number of pages12
JournalJournal of the American Society of Nephrology
Volume20
Issue number12
DOIs
Publication statusPublished - Dec 1 2009

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ASJC Scopus subject areas

  • Nephrology

Cite this

Menke, J., Rabacal, W. A., Byrne, K. T., Iwata, Y., Schwartz, M. M., Stanley, E. R., ... Kelley, V. R. (2009). Circulating CSF-1 promotes monocyte and macrophage phenotypes that enhance lupus nephritis. Journal of the American Society of Nephrology, 20(12), 2581-2592. https://doi.org/10.1681/ASN.2009050499