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

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.

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  • Authors+Show Affiliations

    ,

    Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC, USA.

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    Source

    MeSH

    Adult
    Animals
    Biopsy
    Cell Line
    Endothelial Cells
    Female
    Genes, Reporter
    Hedgehog Proteins
    Humans
    Immunohistochemistry
    Kupffer Cells
    Ligands
    Liver
    Liver Cirrhosis
    Macrophage Activation
    Macrophages
    Male
    Mice
    Middle Aged
    Myofibroblasts
    Neovascularization, Pathologic
    Rats
    Real-Time Polymerase Chain Reaction
    Schistosoma mansoni
    Schistosomiasis mansoni
    Severity of Illness Index
    Signal Transduction
    Transfection
    Ultrasonography
    Young Adult

    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 -