Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion
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Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion. / Höchst, Bastian; Schildberg, Frank A; Sauerborn, Pia; Gäbel, Yvonne A; Gevensleben, Heidrun; Goltz, Diane; Heukamp, Lukas C; Türler, Andreas; Ballmaier, Matthias; Gieseke, Friederike; Müller, Ingo; Kalff, Jörg; Kurts, Christian; Knolle, Percy A; Diehl, Linda.
in: J HEPATOL, Jahrgang 59, Nr. 3, 01.09.2013, S. 528-35.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - Activated human hepatic stellate cells induce myeloid derived suppressor cells from peripheral blood monocytes in a CD44-dependent fashion
AU - Höchst, Bastian
AU - Schildberg, Frank A
AU - Sauerborn, Pia
AU - Gäbel, Yvonne A
AU - Gevensleben, Heidrun
AU - Goltz, Diane
AU - Heukamp, Lukas C
AU - Türler, Andreas
AU - Ballmaier, Matthias
AU - Gieseke, Friederike
AU - Müller, Ingo
AU - Kalff, Jörg
AU - Kurts, Christian
AU - Knolle, Percy A
AU - Diehl, Linda
N1 - Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
PY - 2013/9/1
Y1 - 2013/9/1
N2 - BACKGROUND & AIMS: Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells associated with the suppression of immunity. However, little is known about how or where MDSCs are induced and from which cells they originate. The liver is known for its immune regulatory functions. Here, we investigated the capacity of human hepatic stellate cells (HSCs) to transform peripheral blood monocytes into MDSCs.METHODS: We cultured freshly isolated human monocytes from healthy donors on primary human HSCs or an HSC cell-line and characterized the phenotype and function of resulting CD14(+)HLA-DR(-/low) monocytes by flow cytometry, quantitative PCR, and functional assays. We analyzed the molecular mechanisms underlying the induction and function of the CD14(+)HLA-DR(-/low) cells by using blocking antibodies or knock-down technology.RESULTS: Mature peripheral blood monocytes co-cultured with HSCs downregulated HLA-DR and developed a phenotypic and functional profile similar to MDSCs. Only activated but not freshly isolated HSCs were capable of inducing CD14(+)HLA-DR(-/low) cells. Such CD14(+)HLA-DR(-/low) monocyte-derived MDSCs suppressed T-cell proliferation in an arginase-1 dependent fashion. HSC-induced development of CD14(+)HLA-DR(-/low) monocyte-derived MDSCs was not mediated by soluble factors, but required physical interaction and was abrogated by blocking CD44.CONCLUSIONS: Our study shows that activated human HSCs convert mature peripheral blood monocytes into MDSCs. As HSCs are activated during chronic inflammation, the subsequent local induction of MDSCs may prevent ensuing excessive liver injury. HSC-induced MDSCs functionally and phenotypically resemble those isolated from liver cancer patients. Thus, our data suggest that local generation of MDSCs by liver-resident HSCs may contribute to immune suppression during inflammation and cancer in the liver.
AB - BACKGROUND & AIMS: Myeloid derived suppressor cells (MDSCs) are a heterogeneous population of cells associated with the suppression of immunity. However, little is known about how or where MDSCs are induced and from which cells they originate. The liver is known for its immune regulatory functions. Here, we investigated the capacity of human hepatic stellate cells (HSCs) to transform peripheral blood monocytes into MDSCs.METHODS: We cultured freshly isolated human monocytes from healthy donors on primary human HSCs or an HSC cell-line and characterized the phenotype and function of resulting CD14(+)HLA-DR(-/low) monocytes by flow cytometry, quantitative PCR, and functional assays. We analyzed the molecular mechanisms underlying the induction and function of the CD14(+)HLA-DR(-/low) cells by using blocking antibodies or knock-down technology.RESULTS: Mature peripheral blood monocytes co-cultured with HSCs downregulated HLA-DR and developed a phenotypic and functional profile similar to MDSCs. Only activated but not freshly isolated HSCs were capable of inducing CD14(+)HLA-DR(-/low) cells. Such CD14(+)HLA-DR(-/low) monocyte-derived MDSCs suppressed T-cell proliferation in an arginase-1 dependent fashion. HSC-induced development of CD14(+)HLA-DR(-/low) monocyte-derived MDSCs was not mediated by soluble factors, but required physical interaction and was abrogated by blocking CD44.CONCLUSIONS: Our study shows that activated human HSCs convert mature peripheral blood monocytes into MDSCs. As HSCs are activated during chronic inflammation, the subsequent local induction of MDSCs may prevent ensuing excessive liver injury. HSC-induced MDSCs functionally and phenotypically resemble those isolated from liver cancer patients. Thus, our data suggest that local generation of MDSCs by liver-resident HSCs may contribute to immune suppression during inflammation and cancer in the liver.
KW - Antigens, CD14
KW - Antigens, CD44
KW - Arginase
KW - Cell Communication
KW - Cell Differentiation
KW - Cell Line
KW - Cell Proliferation
KW - Coculture Techniques
KW - Down-Regulation
KW - HLA-DR Antigens
KW - Hepatic Stellate Cells
KW - Humans
KW - Immune Tolerance
KW - Lymphocyte Activation
KW - Monocytes
KW - Myeloid Cells
KW - T-Lymphocytes
U2 - 10.1016/j.jhep.2013.04.033
DO - 10.1016/j.jhep.2013.04.033
M3 - SCORING: Journal article
C2 - 23665041
VL - 59
SP - 528
EP - 535
JO - J HEPATOL
JF - J HEPATOL
SN - 0168-8278
IS - 3
ER -