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 journalArticle

14 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)344-353
Number of pages10
JournalJournal of Hepatology
Volume65
Issue number2
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

Fingerprint

Interleukin-15 Receptors
Interleukin-15
Hepatic Stellate Cells
Interleukin-15 Receptor alpha Subunit
Homeostasis
Liver
Knockout Mice
Natural Killer T-Cells
Fibrosis
Collagen
Natural Killer Cells
Cicatrix
Hepatocytes
Liver Regeneration
Microarray Analysis
Bone Marrow Transplantation
Radio
Transcriptome
Liver Cirrhosis
Transforming Growth Factor beta

Keywords

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

ASJC Scopus subject areas

  • Hepatology

Cite this

Jiao, J., Ooka, K., Fey, H., Fiel, M. I., Rahmman, A. H., Kojima, K., ... 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

Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice. / Jiao, Jingjing; Ooka, Kohtaro; Fey, Holger; Fiel, Maria Isabel; Rahmman, Adeeb H.; Kojima, Kensuke; Hoshida, Yujin; Chen, Xintong; de Paula, Tatiana; Vetter, Diana; Sastre, David; Lee, Ka Hin; Lee, Youngmin A.; Bansal, Meena; Friedman, Scott L.; Merad, Miriam; Aloman, Costica.

In: Journal of Hepatology, Vol. 65, No. 2, 01.08.2016, p. 344-353.

Research output: Contribution to journalArticle

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
Jiao, Jingjing ; Ooka, Kohtaro ; Fey, Holger ; Fiel, Maria Isabel ; Rahmman, Adeeb H. ; Kojima, Kensuke ; Hoshida, Yujin ; Chen, Xintong ; de Paula, Tatiana ; Vetter, Diana ; Sastre, David ; Lee, Ka Hin ; Lee, Youngmin A. ; Bansal, Meena ; Friedman, Scott L. ; Merad, Miriam ; Aloman, Costica. / Interleukin-15 receptor α on hepatic stellate cells regulates hepatic fibrogenesis in mice. In: Journal of Hepatology. 2016 ; Vol. 65, No. 2. pp. 344-353.
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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

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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.

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KW - Hepatic stellate cells

KW - Interleukin 15

KW - Mice

KW - NK cells

KW - NKT cells

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