Distinct roles of CSF-1 isoforms in lupus nephritis

Julia Menke, Yasunori Iwata, Whitney A. Rabacal, Ranu Basu, E. Richard Stanley, Vicki Rubin Kelley

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Colony-stimulating factor-1 (CSF-1), the principal growth factor for macrophages, is increased in the kidney, serum, and urine of patients with lupus nephritis, and eliminating CSF-1 suppresses lupus in MRL-Fas lpr mice. CSF-1 has three biologically active isoforms: a membrane-spanning cell surface glycoprotein (csCSF-1), a secreted proteoglycan (spCSF-1), and a secreted glycoprotein (sgCSF-1); the role of each isoform in the circulation and kidney in autoimmune disease is not well understood. Here, we constructed mutant MRL-Fas lpr mice that only express csCSF-1 or precursors of the spCSF-1 and sgCSF-1 isoforms. Both csCSF-1 and spCSF-1 shifted monocytes toward proinflammatory, activated populations, enhancing their recruitment into the kidney during lupus nephritis. With advancing lupus nephritis, spCSF-1 was the predominant isoform responsible for increasing circulating CSF-1 and, along with the csCSF-1 isoform, for increasing intrarenal CSF-1. Thus, csCSF-1 appears to initiate and promote the local activation of macrophages within the kidney. Intrarenal expression of csCSF-1 and spCSF-1 increases with advancing nephritis, thereby promoting the intrarenal recruitment of monocytes and expansion of Ly6C hi macrophages, which induce apoptosis of the renal parenchyma. Taken together, these data suggest that the three CSF-1 isoforms have distinct biologic properties, suggesting that blocking both circulating and intrarenal CSF-1 may be necessary for therapeutic efficacy.

Original languageEnglish (US)
Pages (from-to)1821-1833
Number of pages13
JournalJournal of the American Society of Nephrology
Volume22
Issue number10
DOIs
StatePublished - Oct 1 2011

ASJC Scopus subject areas

  • Nephrology

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    Menke, J., Iwata, Y., Rabacal, W. A., Basu, R., Stanley, E. R., & Kelley, V. R. (2011). Distinct roles of CSF-1 isoforms in lupus nephritis. Journal of the American Society of Nephrology, 22(10), 1821-1833. https://doi.org/10.1681/ASN.2011010038