Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis

Neil C. Henderson, Alison C. Mackinnon, Sarah L. Farnworth, Tiina Kipari, Christopher Haslett, John P. Iredale, Fu-Tong Liu, Jeremy Hughes, Tariq Sethi

Research output: Contribution to journalArticle

305 Citations (Scopus)

Abstract

Macrophages have been proposed as a key cell type in the pathogenesis of renal fibrosis; however, the mechanism by which macrophages drive fibrosis is still unclear. We show that expression of galectin-3, a β-galactoside- binding lectin, is up-regulated in a mouse model of progressive renal fibrosis (unilateral ureteric obstruction, UUO), and absence of galectin-3 protects against renal myofibroblast accumulation/activation and fibrosis. Furthermore, specific depletion of macrophages using CD11b-DTR mice reduces fibrosis severity after UUO demonstrating that macrophages are key cells in the pathogenesis of renal fibrosis. Disruption of the galectin-3 gene does not affect macrophage recruitment after UUO, or macrophage proinflammatory cytokine profiles in response to interferon-γ/lipopolysaccharide. In addition, absence of galectin-3 does not affect transforming growth factor-β expression or Smad 2/3 phosphorylation in obstructed kidneys. Adoptive transfer of wild-type but not galectin-3-/- macrophages did, however, restore the fibrotic phenotype in galectin-3-/- mice. Cross-over experiments using wild-type and galectin-3-/- macrophage supernatants and renal fibroblasts confirmed that secretion of galectin-3 by macrophages is critical in the activation of renal fibroblasts to a profibrotic phenotype. Therefore,we demonstrate for the first time that galectin-3 expression and secretion by macrophages is a major mechanism linking macrophages to the promotion of renal fibrosis.

Original languageEnglish (US)
Pages (from-to)288-298
Number of pages11
JournalAmerican Journal of Pathology
Volume172
Issue number2
DOIs
StatePublished - Feb 2008

Fingerprint

Galectin 3
Fibrosis
Macrophages
Kidney
Fibroblasts
Phenotype
Galactosides
Myofibroblasts
Adoptive Transfer
Transforming Growth Factors
Lectins
Interferons
Lipopolysaccharides
Phosphorylation

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Henderson, N. C., Mackinnon, A. C., Farnworth, S. L., Kipari, T., Haslett, C., Iredale, J. P., ... Sethi, T. (2008). Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. American Journal of Pathology, 172(2), 288-298. https://doi.org/10.2353/ajpath.2008.070726

Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. / Henderson, Neil C.; Mackinnon, Alison C.; Farnworth, Sarah L.; Kipari, Tiina; Haslett, Christopher; Iredale, John P.; Liu, Fu-Tong; Hughes, Jeremy; Sethi, Tariq.

In: American Journal of Pathology, Vol. 172, No. 2, 02.2008, p. 288-298.

Research output: Contribution to journalArticle

Henderson, NC, Mackinnon, AC, Farnworth, SL, Kipari, T, Haslett, C, Iredale, JP, Liu, F-T, Hughes, J & Sethi, T 2008, 'Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis', American Journal of Pathology, vol. 172, no. 2, pp. 288-298. https://doi.org/10.2353/ajpath.2008.070726
Henderson NC, Mackinnon AC, Farnworth SL, Kipari T, Haslett C, Iredale JP et al. Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. American Journal of Pathology. 2008 Feb;172(2):288-298. https://doi.org/10.2353/ajpath.2008.070726
Henderson, Neil C. ; Mackinnon, Alison C. ; Farnworth, Sarah L. ; Kipari, Tiina ; Haslett, Christopher ; Iredale, John P. ; Liu, Fu-Tong ; Hughes, Jeremy ; Sethi, Tariq. / Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis. In: American Journal of Pathology. 2008 ; Vol. 172, No. 2. pp. 288-298.
@article{c4b8e34149d441ccb89b02ff0079b2f6,
title = "Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis",
abstract = "Macrophages have been proposed as a key cell type in the pathogenesis of renal fibrosis; however, the mechanism by which macrophages drive fibrosis is still unclear. We show that expression of galectin-3, a β-galactoside- binding lectin, is up-regulated in a mouse model of progressive renal fibrosis (unilateral ureteric obstruction, UUO), and absence of galectin-3 protects against renal myofibroblast accumulation/activation and fibrosis. Furthermore, specific depletion of macrophages using CD11b-DTR mice reduces fibrosis severity after UUO demonstrating that macrophages are key cells in the pathogenesis of renal fibrosis. Disruption of the galectin-3 gene does not affect macrophage recruitment after UUO, or macrophage proinflammatory cytokine profiles in response to interferon-γ/lipopolysaccharide. In addition, absence of galectin-3 does not affect transforming growth factor-β expression or Smad 2/3 phosphorylation in obstructed kidneys. Adoptive transfer of wild-type but not galectin-3-/- macrophages did, however, restore the fibrotic phenotype in galectin-3-/- mice. Cross-over experiments using wild-type and galectin-3-/- macrophage supernatants and renal fibroblasts confirmed that secretion of galectin-3 by macrophages is critical in the activation of renal fibroblasts to a profibrotic phenotype. Therefore,we demonstrate for the first time that galectin-3 expression and secretion by macrophages is a major mechanism linking macrophages to the promotion of renal fibrosis.",
author = "Henderson, {Neil C.} and Mackinnon, {Alison C.} and Farnworth, {Sarah L.} and Tiina Kipari and Christopher Haslett and Iredale, {John P.} and Fu-Tong Liu and Jeremy Hughes and Tariq Sethi",
year = "2008",
month = "2",
doi = "10.2353/ajpath.2008.070726",
language = "English (US)",
volume = "172",
pages = "288--298",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "2",

}

TY - JOUR

T1 - Galectin-3 expression and secretion links macrophages to the promotion of renal fibrosis

AU - Henderson, Neil C.

AU - Mackinnon, Alison C.

AU - Farnworth, Sarah L.

AU - Kipari, Tiina

AU - Haslett, Christopher

AU - Iredale, John P.

AU - Liu, Fu-Tong

AU - Hughes, Jeremy

AU - Sethi, Tariq

PY - 2008/2

Y1 - 2008/2

N2 - Macrophages have been proposed as a key cell type in the pathogenesis of renal fibrosis; however, the mechanism by which macrophages drive fibrosis is still unclear. We show that expression of galectin-3, a β-galactoside- binding lectin, is up-regulated in a mouse model of progressive renal fibrosis (unilateral ureteric obstruction, UUO), and absence of galectin-3 protects against renal myofibroblast accumulation/activation and fibrosis. Furthermore, specific depletion of macrophages using CD11b-DTR mice reduces fibrosis severity after UUO demonstrating that macrophages are key cells in the pathogenesis of renal fibrosis. Disruption of the galectin-3 gene does not affect macrophage recruitment after UUO, or macrophage proinflammatory cytokine profiles in response to interferon-γ/lipopolysaccharide. In addition, absence of galectin-3 does not affect transforming growth factor-β expression or Smad 2/3 phosphorylation in obstructed kidneys. Adoptive transfer of wild-type but not galectin-3-/- macrophages did, however, restore the fibrotic phenotype in galectin-3-/- mice. Cross-over experiments using wild-type and galectin-3-/- macrophage supernatants and renal fibroblasts confirmed that secretion of galectin-3 by macrophages is critical in the activation of renal fibroblasts to a profibrotic phenotype. Therefore,we demonstrate for the first time that galectin-3 expression and secretion by macrophages is a major mechanism linking macrophages to the promotion of renal fibrosis.

AB - Macrophages have been proposed as a key cell type in the pathogenesis of renal fibrosis; however, the mechanism by which macrophages drive fibrosis is still unclear. We show that expression of galectin-3, a β-galactoside- binding lectin, is up-regulated in a mouse model of progressive renal fibrosis (unilateral ureteric obstruction, UUO), and absence of galectin-3 protects against renal myofibroblast accumulation/activation and fibrosis. Furthermore, specific depletion of macrophages using CD11b-DTR mice reduces fibrosis severity after UUO demonstrating that macrophages are key cells in the pathogenesis of renal fibrosis. Disruption of the galectin-3 gene does not affect macrophage recruitment after UUO, or macrophage proinflammatory cytokine profiles in response to interferon-γ/lipopolysaccharide. In addition, absence of galectin-3 does not affect transforming growth factor-β expression or Smad 2/3 phosphorylation in obstructed kidneys. Adoptive transfer of wild-type but not galectin-3-/- macrophages did, however, restore the fibrotic phenotype in galectin-3-/- mice. Cross-over experiments using wild-type and galectin-3-/- macrophage supernatants and renal fibroblasts confirmed that secretion of galectin-3 by macrophages is critical in the activation of renal fibroblasts to a profibrotic phenotype. Therefore,we demonstrate for the first time that galectin-3 expression and secretion by macrophages is a major mechanism linking macrophages to the promotion of renal fibrosis.

UR - http://www.scopus.com/inward/record.url?scp=39549100788&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39549100788&partnerID=8YFLogxK

U2 - 10.2353/ajpath.2008.070726

DO - 10.2353/ajpath.2008.070726

M3 - Article

VL - 172

SP - 288

EP - 298

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 2

ER -