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

Research output: Contribution to journalArticle

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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
StatePublished - Dec 1 2009

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Lupus Nephritis
Macrophage Colony-Stimulating Factor
Monocytes
Macrophages
Phenotype
Kidney Diseases
Urine
Kidney
Serum

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

Circulating CSF-1 promotes monocyte and macrophage phenotypes that enhance lupus nephritis. / Menke, Julia; Rabacal, Whitney A.; Byrne, Katelyn T.; Iwata, Yasunori; Schwartz, Melvin M.; Stanley, E. Richard; Schwarting, Andreas; Kelley, Vicki Rubin.

In: Journal of the American Society of Nephrology, Vol. 20, No. 12, 01.12.2009, p. 2581-2592.

Research output: Contribution to journalArticle

Menke, J, Rabacal, WA, Byrne, KT, Iwata, Y, Schwartz, MM, Stanley, ER, Schwarting, A & Kelley, VR 2009, 'Circulating CSF-1 promotes monocyte and macrophage phenotypes that enhance lupus nephritis', Journal of the American Society of Nephrology, vol. 20, no. 12, pp. 2581-2592. https://doi.org/10.1681/ASN.2009050499
Menke, Julia ; Rabacal, Whitney A. ; Byrne, Katelyn T. ; Iwata, Yasunori ; Schwartz, Melvin M. ; Stanley, E. Richard ; Schwarting, Andreas ; Kelley, Vicki Rubin. / Circulating CSF-1 promotes monocyte and macrophage phenotypes that enhance lupus nephritis. In: Journal of the American Society of Nephrology. 2009 ; Vol. 20, No. 12. pp. 2581-2592.
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