Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice

Jingjing Jiao; Kohtaro Ooka; Holger Fey; Maria Isabel Fiel; Adeeb H. Rahmman; Kensuke Kojima; Yujin Hoshida; Xintong Chen; Tatiana de Paula; Diana Vetter; David Sastre; Ka Hin Lee; Youngmin A. Lee; Meena Bansal; Scott L. Friedman; Miriam Merad; Costica Aloman

doi:10.1016/j.jhep.2016.04.020

Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice

Jingjing Jiao, Kohtaro Ooka, Holger Fey, Maria Isabel Fiel, Adeeb H. Rahmman, Kensuke Kojima, Yujin Hoshida, Xintong Chen, Tatiana de Paula, Diana Vetter, David Sastre, Ka Hin Lee, Youngmin A. Lee, Meena Bansal, Scott L. Friedman, Miriam Merad, Costica Aloman

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

29 Scopus citations

Abstract

Background & Aims Interleukin-15 (IL-15) and its high affinity receptor interleukin-15 receptor alpha (IL-15Rα) are widely expressed in immune cells and hepatic resident cells. IL-15 signaling has important functions in homeostasis of natural killer (NK), natural killer T (NKT) and cytotoxic T (CD8⁺ T) cells, and in liver regeneration. We hypothesized that IL-15 has a protective role in liver fibrosis progression by maintaining NK cell homeostasis. Methods Fibrosis was induced using two mechanistically distinct models. Congenic bone marrow transplantation was used to evaluate the contribution of IL-15 signaling from various compartments to NK, CD8⁺ T and NKT cell homeostasis and fibrogenesis. The gene expression profile of hepatic stellate cell (HSC) from IL-15Rα knockout (IL-15RαKO) mice and wild-type mice were captured using microarray analysis and validated in isolated HSC. Quantitative real-time PCR was used to assess repressors of collagen transcription. Results IL-15RαKO mice exhibited more fibrosis in both models. IL-15 signaling from specific types of hepatic cells had divergent roles in maintaining liver NK, CD8⁺ T and NKT cells, with a direct and protective role on radio-resistant non-parenchymal cells beyond the control of NK homeostasis. HSCs isolated from IL-15RαKO mice demonstrated upregulation of collagen production. Finally, IL-15RαKO HSC with or without transforming growth factor beta (TGF-β) stimulation exhibited increased expression of fibrosis markers and decreased collagen transcription repressors expression. Conclusions IL-15Rα signaling has a direct anti-fibrotic effect independent of preserving NK homeostasis. These findings establish a rationale to further explore the anti-fibrotic potential of enhancing IL-15 signaling in HSCs. Lay summary We investigated how a cellular protein, Interleukin-15 (IL-15), decreases the amount of scar tissue that is formed upon liver injury. We found that IL-15 and its receptor decrease the amount of scar tissue that is created by specialized liver cells (called stellate cells) and increase the number of a specific subgroup of immune cells (natural killer cells) that are known to eliminate stellate cells. Transcript profiling accession number GSE45612, GSE 68001 and GSE 25097.

Original language	English (US)
Pages (from-to)	344-353
Number of pages	10
Journal	Journal of Hepatology
Volume	65
Issue number	2
DOIs	https://doi.org/10.1016/j.jhep.2016.04.020
State	Published - Aug 1 2016
Externally published	Yes

Keywords

Collagen
Fibrosis
Hepatic stellate cells
Interleukin 15
Mice
NK cells
NKT cells

ASJC Scopus subject areas

Hepatology

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10.1016/j.jhep.2016.04.020

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Jiao, J., Ooka, K., Fey, H., Fiel, M. I., Rahmman, A. H., Kojima, K., Hoshida, Y., Chen, X., de Paula, T., Vetter, D., Sastre, D., Lee, K. H., Lee, Y. A., Bansal, M., Friedman, S. L., Merad, M., & Aloman, C. (2016). Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice. Journal of Hepatology, 65(2), 344-353. https://doi.org/10.1016/j.jhep.2016.04.020

Jiao, J, Ooka, K, Fey, H, Fiel, MI, Rahmman, AH, Kojima, K, Hoshida, Y, Chen, X, de Paula, T, Vetter, D, Sastre, D, Lee, KH, Lee, YA, Bansal, M, Friedman, SL, Merad, M & Aloman, C 2016, 'Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice', Journal of Hepatology, vol. 65, no. 2, pp. 344-353. https://doi.org/10.1016/j.jhep.2016.04.020

@article{b1c30108c7044e2da953b610a42b938e,

title = "Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice",

abstract = "Background & Aims Interleukin-15 (IL-15) and its high affinity receptor interleukin-15 receptor alpha (IL-15Rα) are widely expressed in immune cells and hepatic resident cells. IL-15 signaling has important functions in homeostasis of natural killer (NK), natural killer T (NKT) and cytotoxic T (CD8+ T) cells, and in liver regeneration. We hypothesized that IL-15 has a protective role in liver fibrosis progression by maintaining NK cell homeostasis. Methods Fibrosis was induced using two mechanistically distinct models. Congenic bone marrow transplantation was used to evaluate the contribution of IL-15 signaling from various compartments to NK, CD8+ T and NKT cell homeostasis and fibrogenesis. The gene expression profile of hepatic stellate cell (HSC) from IL-15Rα knockout (IL-15RαKO) mice and wild-type mice were captured using microarray analysis and validated in isolated HSC. Quantitative real-time PCR was used to assess repressors of collagen transcription. Results IL-15RαKO mice exhibited more fibrosis in both models. IL-15 signaling from specific types of hepatic cells had divergent roles in maintaining liver NK, CD8+ T and NKT cells, with a direct and protective role on radio-resistant non-parenchymal cells beyond the control of NK homeostasis. HSCs isolated from IL-15RαKO mice demonstrated upregulation of collagen production. Finally, IL-15RαKO HSC with or without transforming growth factor beta (TGF-β) stimulation exhibited increased expression of fibrosis markers and decreased collagen transcription repressors expression. Conclusions IL-15Rα signaling has a direct anti-fibrotic effect independent of preserving NK homeostasis. These findings establish a rationale to further explore the anti-fibrotic potential of enhancing IL-15 signaling in HSCs. Lay summary We investigated how a cellular protein, Interleukin-15 (IL-15), decreases the amount of scar tissue that is formed upon liver injury. We found that IL-15 and its receptor decrease the amount of scar tissue that is created by specialized liver cells (called stellate cells) and increase the number of a specific subgroup of immune cells (natural killer cells) that are known to eliminate stellate cells. Transcript profiling accession number GSE45612, GSE 68001 and GSE 25097.",

keywords = "Collagen, Fibrosis, Hepatic stellate cells, Interleukin 15, Mice, NK cells, NKT cells",

author = "Jingjing Jiao and Kohtaro Ooka and Holger Fey and Fiel, {Maria Isabel} and Rahmman, {Adeeb H.} and Kensuke Kojima and Yujin Hoshida and Xintong Chen and {de Paula}, Tatiana and Diana Vetter and David Sastre and Lee, {Ka Hin} and Lee, {Youngmin A.} and Meena Bansal and Friedman, {Scott L.} and Miriam Merad and Costica Aloman",

note = "Funding Information: This work was supported by funds from NIH K08DK088954-01A1 (to CA); NIH DK56621 and 1K05AA018408-01 (to SLF); CA112100 and HL086899 (to MM); NIH/NIDDK (DK099558), Irma T. Hirschl Trust, Dr. Harold and Golden Lamport Research Award (to YH). This work was partially supported by funds from UTHealth Innovation in Cancer Prevention Research Training Program Post-doctoral Fellowship (Cancer Prevention and Research Institute of Texas grant # RP140103 (to JJ)). Part of this work was presented in abstract form at the 2011 and 2015 Annual Meetings of the American Association for the Study of Liver Diseases. Publisher Copyright: {\textcopyright} 2016 European Association for the Study of the Liver",

year = "2016",

month = aug,

day = "1",

doi = "10.1016/j.jhep.2016.04.020",

language = "English (US)",

volume = "65",

pages = "344--353",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

number = "2",

}

TY - JOUR

T1 - Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice

AU - Jiao, Jingjing

AU - Ooka, Kohtaro

AU - Fey, Holger

AU - Fiel, Maria Isabel

AU - Rahmman, Adeeb H.

AU - Kojima, Kensuke

AU - Hoshida, Yujin

AU - Chen, Xintong

AU - de Paula, Tatiana

AU - Vetter, Diana

AU - Sastre, David

AU - Lee, Ka Hin

AU - Lee, Youngmin A.

AU - Bansal, Meena

AU - Friedman, Scott L.

AU - Merad, Miriam

AU - Aloman, Costica

N1 - Funding Information: This work was supported by funds from NIH K08DK088954-01A1 (to CA); NIH DK56621 and 1K05AA018408-01 (to SLF); CA112100 and HL086899 (to MM); NIH/NIDDK (DK099558), Irma T. Hirschl Trust, Dr. Harold and Golden Lamport Research Award (to YH). This work was partially supported by funds from UTHealth Innovation in Cancer Prevention Research Training Program Post-doctoral Fellowship (Cancer Prevention and Research Institute of Texas grant # RP140103 (to JJ)). Part of this work was presented in abstract form at the 2011 and 2015 Annual Meetings of the American Association for the Study of Liver Diseases. Publisher Copyright: © 2016 European Association for the Study of the Liver

PY - 2016/8/1

Y1 - 2016/8/1

N2 - Background & Aims Interleukin-15 (IL-15) and its high affinity receptor interleukin-15 receptor alpha (IL-15Rα) are widely expressed in immune cells and hepatic resident cells. IL-15 signaling has important functions in homeostasis of natural killer (NK), natural killer T (NKT) and cytotoxic T (CD8+ T) cells, and in liver regeneration. We hypothesized that IL-15 has a protective role in liver fibrosis progression by maintaining NK cell homeostasis. Methods Fibrosis was induced using two mechanistically distinct models. Congenic bone marrow transplantation was used to evaluate the contribution of IL-15 signaling from various compartments to NK, CD8+ T and NKT cell homeostasis and fibrogenesis. The gene expression profile of hepatic stellate cell (HSC) from IL-15Rα knockout (IL-15RαKO) mice and wild-type mice were captured using microarray analysis and validated in isolated HSC. Quantitative real-time PCR was used to assess repressors of collagen transcription. Results IL-15RαKO mice exhibited more fibrosis in both models. IL-15 signaling from specific types of hepatic cells had divergent roles in maintaining liver NK, CD8+ T and NKT cells, with a direct and protective role on radio-resistant non-parenchymal cells beyond the control of NK homeostasis. HSCs isolated from IL-15RαKO mice demonstrated upregulation of collagen production. Finally, IL-15RαKO HSC with or without transforming growth factor beta (TGF-β) stimulation exhibited increased expression of fibrosis markers and decreased collagen transcription repressors expression. Conclusions IL-15Rα signaling has a direct anti-fibrotic effect independent of preserving NK homeostasis. These findings establish a rationale to further explore the anti-fibrotic potential of enhancing IL-15 signaling in HSCs. Lay summary We investigated how a cellular protein, Interleukin-15 (IL-15), decreases the amount of scar tissue that is formed upon liver injury. We found that IL-15 and its receptor decrease the amount of scar tissue that is created by specialized liver cells (called stellate cells) and increase the number of a specific subgroup of immune cells (natural killer cells) that are known to eliminate stellate cells. Transcript profiling accession number GSE45612, GSE 68001 and GSE 25097.

AB - Background & Aims Interleukin-15 (IL-15) and its high affinity receptor interleukin-15 receptor alpha (IL-15Rα) are widely expressed in immune cells and hepatic resident cells. IL-15 signaling has important functions in homeostasis of natural killer (NK), natural killer T (NKT) and cytotoxic T (CD8+ T) cells, and in liver regeneration. We hypothesized that IL-15 has a protective role in liver fibrosis progression by maintaining NK cell homeostasis. Methods Fibrosis was induced using two mechanistically distinct models. Congenic bone marrow transplantation was used to evaluate the contribution of IL-15 signaling from various compartments to NK, CD8+ T and NKT cell homeostasis and fibrogenesis. The gene expression profile of hepatic stellate cell (HSC) from IL-15Rα knockout (IL-15RαKO) mice and wild-type mice were captured using microarray analysis and validated in isolated HSC. Quantitative real-time PCR was used to assess repressors of collagen transcription. Results IL-15RαKO mice exhibited more fibrosis in both models. IL-15 signaling from specific types of hepatic cells had divergent roles in maintaining liver NK, CD8+ T and NKT cells, with a direct and protective role on radio-resistant non-parenchymal cells beyond the control of NK homeostasis. HSCs isolated from IL-15RαKO mice demonstrated upregulation of collagen production. Finally, IL-15RαKO HSC with or without transforming growth factor beta (TGF-β) stimulation exhibited increased expression of fibrosis markers and decreased collagen transcription repressors expression. Conclusions IL-15Rα signaling has a direct anti-fibrotic effect independent of preserving NK homeostasis. These findings establish a rationale to further explore the anti-fibrotic potential of enhancing IL-15 signaling in HSCs. Lay summary We investigated how a cellular protein, Interleukin-15 (IL-15), decreases the amount of scar tissue that is formed upon liver injury. We found that IL-15 and its receptor decrease the amount of scar tissue that is created by specialized liver cells (called stellate cells) and increase the number of a specific subgroup of immune cells (natural killer cells) that are known to eliminate stellate cells. Transcript profiling accession number GSE45612, GSE 68001 and GSE 25097.

KW - Collagen

KW - Fibrosis

KW - Hepatic stellate cells

KW - Interleukin 15

KW - Mice

KW - NK cells

KW - NKT cells

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DO - 10.1016/j.jhep.2016.04.020

M3 - Article

C2 - 27154062

AN - SCOPUS:84990852873

SN - 0168-8278

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JO - Journal of Hepatology

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Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice

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