Macrophage-derived hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni
Article first published online: 1 NOV 2012
© 2012 John Wiley & Sons A/S
Volume 33, Issue 1, pages 149–161, January 2013
How to Cite
Pereira, T. A., Xie, G., Choi, S. S., Syn, W.-K., Voieta, I., Lu, J., Chan, I. S., Swiderska, M., Amaral, K. B., Antunes, C. M., Secor, W. E., Witek, R. P., Lambertucci, J. R., Pereira, F. L. and Diehl, A. M. (2013), Macrophage-derived hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni. Liver International, 33: 149–161. doi: 10.1111/liv.12016
- Issue published online: 10 DEC 2012
- Article first published online: 1 NOV 2012
- Accepted manuscript online: 8 OCT 2012 09:15PM EST
- Manuscript Accepted: 1 AUG 2012
- Manuscript Received: 23 FEB 2012
- NIH. Grant Numbers: R01 DK077794, 5K08 DK080980
- Brazilian government
- alternative activation of macrophages;
- hedgehog pathway;
- schistosomiasis mansoni;
- vascular remodelling
Schistosomiasis mansoni is a major cause of portal fibrosis and portal hypertension. The Hedgehog pathway regulates fibrogenic repair in some types of liver injury.
Determine if Hedgehog pathway activation occurs during fibrosis progression in schistosomiasis and to determine if macrophage-related mechanisms are involved.
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.
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.
SEA stimulates liver macrophages to produce Hh ligands, which promote alternative activation of macrophages, fibrogenesis and vascular remodelling in schistosomiasis.