Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC

Alaa Melhem; Nidal Muhanna; Amal Bishara; Carlos E. Alvarez; Yaron Ilan; Taiser Bishara; Amjad Horani; Mithal Nassar; Scott L. Friedman; Rifaat Safadi

doi:10.1016/j.jhep.2005.12.025

Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC

Alaa Melhem, Nidal Muhanna, Amal Bishara, Carlos E. Alvarez, Yaron Ilan, Taiser Bishara, Amjad Horani, Mithal Nassar, Scott L. Friedman, Rifaat Safadi

Research output: Contribution to journal › Article › peer-review

239 Scopus citations

Abstract

Background/Aims: We have investigated the role of natural killer (NK) cells in hepatic fibrogenesis. Mouse NK cells express both inhibitory/activating-killing-immunoglobulin-related-receptors (iKIR/aKIR) specific for Class-I-molecules. Methods: Hepatic fibrosis induced by carbon-tetrachloride (CCl₄) was compared between wild-type (WT) male-BALBc; combined-immunodeficiency (SCID, lacking B/T-cells); and SCID-BEIGE-mice (lacking B/T/NK cells), and naive mice. Results: Hepatic fibrosis significantly increased in all CCl₄-treated groups. SCID-BEIGE mice had more fibrosis than SCID-mice (P < 0.0001) as assessed by morphometry of sirius-red stained tissue sections. Following fibrosis, hepatic NK cells significantly decreased, the aKIR:iKIR-ratio significantly increased while Class-I expression on HSC decreased (P < 0.001). Both freshly isolated and in situ HSC displayed a significant increase in cellular apoptosis following fibrosis induction. Confocal microscopy demonstrated the direct adhesion of NK cells to HSC in mouse liver sections and in vitro human NK/HSC co-culture. In human HSC there was decreased Class-I expression and increased apoptosis as well, which was further increased following blocking of either HSC-related Class-I or NK-related killer inhibitory receptors. Apoptosis was inhibited by pre-incubation of NK cells with the granzyme inhibitor 3,4-dichloroisocoumarin. Conclusions: During liver injury, NK cells have an anti-fibrotic activity at least in part through stimulation of HSC killing.

Original language	English
Pages (from-to)	60-71
Number of pages	12
Journal	Journal of Hepatology
Volume	45
Issue number	1
DOIs	https://doi.org/10.1016/j.jhep.2005.12.025
State	Published - Jul 2006

Keywords

Hepatic fibrosis
Hepatic stellate cells
KIR
Lymphocytes
NK cells
SCID

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@article{528e1954868447ad9100036b5a5f8a0f,

title = "Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC",

abstract = "Background/Aims: We have investigated the role of natural killer (NK) cells in hepatic fibrogenesis. Mouse NK cells express both inhibitory/activating-killing-immunoglobulin-related-receptors (iKIR/aKIR) specific for Class-I-molecules. Methods: Hepatic fibrosis induced by carbon-tetrachloride (CCl4) was compared between wild-type (WT) male-BALBc; combined-immunodeficiency (SCID, lacking B/T-cells); and SCID-BEIGE-mice (lacking B/T/NK cells), and naive mice. Results: Hepatic fibrosis significantly increased in all CCl4-treated groups. SCID-BEIGE mice had more fibrosis than SCID-mice (P < 0.0001) as assessed by morphometry of sirius-red stained tissue sections. Following fibrosis, hepatic NK cells significantly decreased, the aKIR:iKIR-ratio significantly increased while Class-I expression on HSC decreased (P < 0.001). Both freshly isolated and in situ HSC displayed a significant increase in cellular apoptosis following fibrosis induction. Confocal microscopy demonstrated the direct adhesion of NK cells to HSC in mouse liver sections and in vitro human NK/HSC co-culture. In human HSC there was decreased Class-I expression and increased apoptosis as well, which was further increased following blocking of either HSC-related Class-I or NK-related killer inhibitory receptors. Apoptosis was inhibited by pre-incubation of NK cells with the granzyme inhibitor 3,4-dichloroisocoumarin. Conclusions: During liver injury, NK cells have an anti-fibrotic activity at least in part through stimulation of HSC killing.",

keywords = "Hepatic fibrosis, Hepatic stellate cells, KIR, Lymphocytes, NK cells, SCID",

author = "Alaa Melhem and Nidal Muhanna and Amal Bishara and Alvarez, {Carlos E.} and Yaron Ilan and Taiser Bishara and Amjad Horani and Mithal Nassar and Friedman, {Scott L.} and Rifaat Safadi",

note = "Funding Information: This work was supported by grants from {\textquoteleft}Return to Hadassah,{\textquoteright} {\textquoteleft}Compensatory{\textquoteright} and {\textquoteleft}Salzburg{\textquoteright} Awards, the Israel Science Foundation (grant No.8033601, 8033603, 8033604 to RS), The Feld Fibrosis Foundation at Mount Sinai, and the National Institutes of Health (DK56621 to SLF). ",

year = "2006",

month = jul,

doi = "10.1016/j.jhep.2005.12.025",

language = "English",

volume = "45",

pages = "60--71",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

number = "1",

}

TY - JOUR

T1 - Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC

AU - Melhem, Alaa

AU - Muhanna, Nidal

AU - Bishara, Amal

AU - Alvarez, Carlos E.

AU - Ilan, Yaron

AU - Bishara, Taiser

AU - Horani, Amjad

AU - Nassar, Mithal

AU - Friedman, Scott L.

AU - Safadi, Rifaat

N1 - Funding Information: This work was supported by grants from ‘Return to Hadassah,’ ‘Compensatory’ and ‘Salzburg’ Awards, the Israel Science Foundation (grant No.8033601, 8033603, 8033604 to RS), The Feld Fibrosis Foundation at Mount Sinai, and the National Institutes of Health (DK56621 to SLF).

PY - 2006/7

Y1 - 2006/7

N2 - Background/Aims: We have investigated the role of natural killer (NK) cells in hepatic fibrogenesis. Mouse NK cells express both inhibitory/activating-killing-immunoglobulin-related-receptors (iKIR/aKIR) specific for Class-I-molecules. Methods: Hepatic fibrosis induced by carbon-tetrachloride (CCl4) was compared between wild-type (WT) male-BALBc; combined-immunodeficiency (SCID, lacking B/T-cells); and SCID-BEIGE-mice (lacking B/T/NK cells), and naive mice. Results: Hepatic fibrosis significantly increased in all CCl4-treated groups. SCID-BEIGE mice had more fibrosis than SCID-mice (P < 0.0001) as assessed by morphometry of sirius-red stained tissue sections. Following fibrosis, hepatic NK cells significantly decreased, the aKIR:iKIR-ratio significantly increased while Class-I expression on HSC decreased (P < 0.001). Both freshly isolated and in situ HSC displayed a significant increase in cellular apoptosis following fibrosis induction. Confocal microscopy demonstrated the direct adhesion of NK cells to HSC in mouse liver sections and in vitro human NK/HSC co-culture. In human HSC there was decreased Class-I expression and increased apoptosis as well, which was further increased following blocking of either HSC-related Class-I or NK-related killer inhibitory receptors. Apoptosis was inhibited by pre-incubation of NK cells with the granzyme inhibitor 3,4-dichloroisocoumarin. Conclusions: During liver injury, NK cells have an anti-fibrotic activity at least in part through stimulation of HSC killing.

AB - Background/Aims: We have investigated the role of natural killer (NK) cells in hepatic fibrogenesis. Mouse NK cells express both inhibitory/activating-killing-immunoglobulin-related-receptors (iKIR/aKIR) specific for Class-I-molecules. Methods: Hepatic fibrosis induced by carbon-tetrachloride (CCl4) was compared between wild-type (WT) male-BALBc; combined-immunodeficiency (SCID, lacking B/T-cells); and SCID-BEIGE-mice (lacking B/T/NK cells), and naive mice. Results: Hepatic fibrosis significantly increased in all CCl4-treated groups. SCID-BEIGE mice had more fibrosis than SCID-mice (P < 0.0001) as assessed by morphometry of sirius-red stained tissue sections. Following fibrosis, hepatic NK cells significantly decreased, the aKIR:iKIR-ratio significantly increased while Class-I expression on HSC decreased (P < 0.001). Both freshly isolated and in situ HSC displayed a significant increase in cellular apoptosis following fibrosis induction. Confocal microscopy demonstrated the direct adhesion of NK cells to HSC in mouse liver sections and in vitro human NK/HSC co-culture. In human HSC there was decreased Class-I expression and increased apoptosis as well, which was further increased following blocking of either HSC-related Class-I or NK-related killer inhibitory receptors. Apoptosis was inhibited by pre-incubation of NK cells with the granzyme inhibitor 3,4-dichloroisocoumarin. Conclusions: During liver injury, NK cells have an anti-fibrotic activity at least in part through stimulation of HSC killing.

KW - Hepatic fibrosis

KW - Hepatic stellate cells

KW - KIR

KW - Lymphocytes

KW - NK cells

KW - SCID

UR - http://www.scopus.com/inward/record.url?scp=33744939234&partnerID=8YFLogxK

U2 - 10.1016/j.jhep.2005.12.025

DO - 10.1016/j.jhep.2005.12.025

M3 - Article

C2 - 16515819

AN - SCOPUS:33744939234

SN - 0168-8278

VL - 45

SP - 60

EP - 71

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 1

ER -

Anti-fibrotic activity of NK cells in experimental liver injury through killing of activated HSC

Abstract

Keywords

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