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

21 Citations (Scopus)

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 2011

Fingerprint

Lupus Nephritis
Macrophage Colony-Stimulating Factor
Protein Isoforms
Inbred MRL lpr Mouse
Kidney
Monocytes
Macrophages
Macrophage Activation
Nephritis
Renal Circulation
Membrane Glycoproteins
Proteoglycans
Autoimmune Diseases
Intercellular Signaling Peptides and Proteins
Glycoproteins
Urine
Apoptosis
Membranes
Serum
Population

ASJC Scopus subject areas

  • Nephrology

Cite this

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

Distinct roles of CSF-1 isoforms in lupus nephritis. / Menke, Julia; Iwata, Yasunori; Rabacal, Whitney A.; Basu, Ranu; Stanley, E. Richard; Kelley, Vicki Rubin.

In: Journal of the American Society of Nephrology, Vol. 22, No. 10, 10.2011, p. 1821-1833.

Research output: Contribution to journalArticle

Menke, J, Iwata, Y, Rabacal, WA, Basu, R, Stanley, ER & Kelley, VR 2011, 'Distinct roles of CSF-1 isoforms in lupus nephritis', Journal of the American Society of Nephrology, vol. 22, no. 10, pp. 1821-1833. https://doi.org/10.1681/ASN.2011010038
Menke J, Iwata Y, Rabacal WA, Basu R, Stanley ER, Kelley VR. Distinct roles of CSF-1 isoforms in lupus nephritis. Journal of the American Society of Nephrology. 2011 Oct;22(10):1821-1833. https://doi.org/10.1681/ASN.2011010038
Menke, Julia ; Iwata, Yasunori ; Rabacal, Whitney A. ; Basu, Ranu ; Stanley, E. Richard ; Kelley, Vicki Rubin. / Distinct roles of CSF-1 isoforms in lupus nephritis. In: Journal of the American Society of Nephrology. 2011 ; Vol. 22, No. 10. pp. 1821-1833.
@article{87bd65fd05c743b4a653624690cbda0b,
title = "Distinct roles of CSF-1 isoforms in lupus nephritis",
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.",
author = "Julia Menke and Yasunori Iwata and Rabacal, {Whitney A.} and Ranu Basu and Stanley, {E. Richard} and Kelley, {Vicki Rubin}",
year = "2011",
month = "10",
doi = "10.1681/ASN.2011010038",
language = "English (US)",
volume = "22",
pages = "1821--1833",
journal = "Journal of the American Society of Nephrology : JASN",
issn = "1046-6673",
publisher = "American Society of Nephrology",
number = "10",

}

TY - JOUR

T1 - Distinct roles of CSF-1 isoforms in lupus nephritis

AU - Menke, Julia

AU - Iwata, Yasunori

AU - Rabacal, Whitney A.

AU - Basu, Ranu

AU - Stanley, E. Richard

AU - Kelley, Vicki Rubin

PY - 2011/10

Y1 - 2011/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=80053557823&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053557823&partnerID=8YFLogxK

U2 - 10.1681/ASN.2011010038

DO - 10.1681/ASN.2011010038

M3 - Article

VL - 22

SP - 1821

EP - 1833

JO - Journal of the American Society of Nephrology : JASN

JF - Journal of the American Society of Nephrology : JASN

SN - 1046-6673

IS - 10

ER -