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Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni.

Publication ,  Journal Article
Pereira, TA; Xie, G; Choi, SS; Syn, W-K; Voieta, I; Lu, J; Chan, IS; Swiderska, M; Amaral, KB; Antunes, CM; Secor, WE; Witek, RP; Pereira, FL ...
Published in: Liver Int
January 2013

BACKGROUND: Schistosomiasis mansoni is a major cause of portal fibrosis and portal hypertension. The Hedgehog pathway regulates fibrogenic repair in some types of liver injury. AIMS: Determine if Hedgehog pathway activation occurs during fibrosis progression in schistosomiasis and to determine if macrophage-related mechanisms are involved. METHODS: Immunohistochemistry was used to characterize the cells that generate and respond to Hedgehog ligands in 28 liver biopsies from patients with different grades of schistosomiasis fibrosis staged by ultrasound. Cultured macrophages (RAW264.7 and primary rat Kupffer cells) and primary rat liver sinusoidal endothelial cells (LSEC) were treated with schistosome egg antigen (SEA) and evaluated using qRT-PCR. Inhibition of the Hedgehog pathway was used to investigate its role in alternative activation of macrophages (M2) and vascular tube formation. RESULTS: Patients with schistosomiasis expressed more ligands (Shh and Ihh) and target genes (Patched and Gli2) than healthy individuals. Activated LSEC and myofibroblasts were Hedgehog responsive [Gli2(+)] and accumulated in parallel with fibrosis stage (P < 0.05). Double IHC for Ihh/CD68 showed that Ihh(+) cells were macrophages. In vitro studies demonstrated that SEA-stimulated macrophages to express Ihh and Shh mRNA (P < 0.05). Conditioned media from such macrophages induced luciferase production by Shh-LightII cells (P < 0.001) and Hedgehog inhibitors blocked this effect (P < 0.001). SEA-treated macrophages also up-regulated their own expression of M2 markers, and Hh pathway inhibitors abrogated this response (P < 0.01). Inhibition of the Hedgehog pathway in LSEC blocked SEA-induced migration and tube formation. CONCLUSION: SEA stimulates liver macrophages to produce Hh ligands, which promote alternative activation of macrophages, fibrogenesis and vascular remodelling in schistosomiasis.

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Published In

Liver Int

DOI

EISSN

1478-3231

Publication Date

January 2013

Volume

33

Issue

1

Start / End Page

149 / 161

Location

United States

Related Subject Headings

  • Young Adult
  • Ultrasonography
  • Transfection
  • Signal Transduction
  • Severity of Illness Index
  • Schistosomiasis mansoni
  • Schistosoma mansoni
  • Real-Time Polymerase Chain Reaction
  • Rats
  • Neovascularization, Pathologic
 

Citation

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ICMJE
MLA
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Pereira, T. A., Xie, G., Choi, S. S., Syn, W.-K., Voieta, I., Lu, J., … Diehl, A. M. (2013). Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni. Liver Int, 33(1), 149–161. https://doi.org/10.1111/liv.12016
Pereira, Thiago A., Guanhua Xie, Steve S. Choi, Wing-Kin Syn, Izabela Voieta, Jiuyi Lu, Isaac S. Chan, et al. “Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni.Liver Int 33, no. 1 (January 2013): 149–61. https://doi.org/10.1111/liv.12016.
Pereira TA, Xie G, Choi SS, Syn W-K, Voieta I, Lu J, et al. Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni. Liver Int. 2013 Jan;33(1):149–61.
Pereira, Thiago A., et al. “Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni.Liver Int, vol. 33, no. 1, Jan. 2013, pp. 149–61. Pubmed, doi:10.1111/liv.12016.
Pereira TA, Xie G, Choi SS, Syn W-K, Voieta I, Lu J, Chan IS, Swiderska M, Amaral KB, Antunes CM, Secor WE, Witek RP, Lambertucci JR, Pereira FL, Diehl AM. Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni. Liver Int. 2013 Jan;33(1):149–161.
Journal cover image

Published In

Liver Int

DOI

EISSN

1478-3231

Publication Date

January 2013

Volume

33

Issue

1

Start / End Page

149 / 161

Location

United States

Related Subject Headings

  • Young Adult
  • Ultrasonography
  • Transfection
  • Signal Transduction
  • Severity of Illness Index
  • Schistosomiasis mansoni
  • Schistosoma mansoni
  • Real-Time Polymerase Chain Reaction
  • Rats
  • Neovascularization, Pathologic