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Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni.
Liver Int 2013; 33(1):149-61LI

Abstract

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.

Authors+Show Affiliations

Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23121638

Citation

Pereira, Thiago A., et al. "Macrophage-derived Hedgehog Ligands Promotes Fibrogenic and Angiogenic Responses in Human Schistosomiasis Mansoni." Liver International : Official Journal of the International Association for the Study of the Liver, vol. 33, no. 1, 2013, pp. 149-61.
Pereira TA, Xie G, Choi SS, et al. Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni. Liver Int. 2013;33(1):149-61.
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 International : Official Journal of the International Association for the Study of the Liver, 33(1), pp. 149-61. doi:10.1111/liv.12016.
Pereira TA, et al. Macrophage-derived Hedgehog Ligands Promotes Fibrogenic and Angiogenic Responses in Human Schistosomiasis Mansoni. Liver Int. 2013;33(1):149-61. PubMed PMID: 23121638.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Macrophage-derived Hedgehog ligands promotes fibrogenic and angiogenic responses in human schistosomiasis mansoni. AU - Pereira,Thiago A, AU - Xie,Guanhua, AU - Choi,Steve S, AU - Syn,Wing-Kin, AU - Voieta,Izabela, AU - Lu,Jiuyi, AU - Chan,Isaac S, AU - Swiderska,Marzena, AU - Amaral,Kirsten B, AU - Antunes,Carlos M, AU - Secor,William E, AU - Witek,Rafal P, AU - Lambertucci,José R, AU - Pereira,Fausto L, AU - Diehl,Anna Mae, Y1 - 2012/11/01/ PY - 2012/02/23/received PY - 2012/08/01/accepted PY - 2012/11/6/entrez PY - 2012/11/6/pubmed PY - 2013/5/23/medline SP - 149 EP - 61 JF - Liver international : official journal of the International Association for the Study of the Liver JO - Liver Int. VL - 33 IS - 1 N2 - 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. SN - 1478-3231 UR - https://www.unboundmedicine.com/medline/citation/23121638/Macrophage_derived_Hedgehog_ligands_promotes_fibrogenic_and_angiogenic_responses_in_human_schistosomiasis_mansoni_ L2 - https://doi.org/10.1111/liv.12016 DB - PRIME DP - Unbound Medicine ER -