Tumor-induced CD11b+ Gr-1+ myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner

Tamar Kapanadze, José Medina-Echeverz, Jaba Gamrekelashvili, Jonathan M. Weiss, Robert H. Wiltrout, Veena Kapoor, Nga Hawk, Masaki Terabe, Jay A. Berzofsky, Michael P. Manns, Ena Wang, Francesco M. Marincola, Firouzeh Korangy, Tim F. Greten

Research output: Contribution to journalArticle

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Abstract

Immunosuppressive CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) accumulate in the livers of tumor-bearing (TB) mice. We studied hepatic MDSCs in two murine models of immune-mediated hepatitis. Unexpectedly, treatment of TB mice with Concanavalin A (Con A) or α-galactosylceramide resulted in increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels in comparison to tumor-free mice. Adoptive transfer of hepatic MDSCs into naïve mice exacerbated Con A induced liver damage. Hepatic CD11b+Gr-1+ cells revealed a polarized proinflammatory gene signature after Con A treatment. An IFN-γ-dependent upregulation of CD40 on hepatic CD11b+Gr-1+ cells along with an upregulation of CD80, CD86, and CD1d after Con A treatment was observed. Con A treatment resulted in a loss of suppressor function by tumor-induced CD11b+Gr-1+ MDSCs as well as enhanced reactive oxygen species (ROS)-mediated hepatotoxicity. CD40 knockdown in hepatic MDSCs led to increased arginase activity upon Con A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40-/- tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased ROS production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSCs act as proinflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner.

Original languageEnglish
Pages (from-to)1148-1158
Number of pages11
JournalEuropean Journal of Immunology
Volume45
Issue number4
DOIs
Publication statusPublished - 1 Apr 2015

Fingerprint

Concanavalin A
Hepatitis
Hepatocytes
Arginase
Neoplasms
Liver
Aspartate Aminotransferases
Alanine Transaminase
Reactive Oxygen Species
Up-Regulation
Galactosylceramides
Therapeutics
Adoptive Transfer
Myeloid Cells
Immunosuppressive Agents
Serum
Myeloid-Derived Suppressor Cells
Genes

Keywords

  • CD40
  • Concanavalin A
  • Immune-mediated hepatitis
  • Myeloid-derived suppressor cells
  • Reactive oxygen species
  • α-Galactosylceramide

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Kapanadze, T., Medina-Echeverz, J., Gamrekelashvili, J., Weiss, J. M., Wiltrout, R. H., Kapoor, V., ... Greten, T. F. (2015). Tumor-induced CD11b+ Gr-1+ myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner. European Journal of Immunology, 45(4), 1148-1158. https://doi.org/10.1002/eji.201445093

Tumor-induced CD11b+ Gr-1+ myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner. / Kapanadze, Tamar; Medina-Echeverz, José; Gamrekelashvili, Jaba; Weiss, Jonathan M.; Wiltrout, Robert H.; Kapoor, Veena; Hawk, Nga; Terabe, Masaki; Berzofsky, Jay A.; Manns, Michael P.; Wang, Ena; Marincola, Francesco M.; Korangy, Firouzeh; Greten, Tim F.

In: European Journal of Immunology, Vol. 45, No. 4, 01.04.2015, p. 1148-1158.

Research output: Contribution to journalArticle

Kapanadze, T, Medina-Echeverz, J, Gamrekelashvili, J, Weiss, JM, Wiltrout, RH, Kapoor, V, Hawk, N, Terabe, M, Berzofsky, JA, Manns, MP, Wang, E, Marincola, FM, Korangy, F & Greten, TF 2015, 'Tumor-induced CD11b+ Gr-1+ myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner', European Journal of Immunology, vol. 45, no. 4, pp. 1148-1158. https://doi.org/10.1002/eji.201445093
Kapanadze, Tamar ; Medina-Echeverz, José ; Gamrekelashvili, Jaba ; Weiss, Jonathan M. ; Wiltrout, Robert H. ; Kapoor, Veena ; Hawk, Nga ; Terabe, Masaki ; Berzofsky, Jay A. ; Manns, Michael P. ; Wang, Ena ; Marincola, Francesco M. ; Korangy, Firouzeh ; Greten, Tim F. / Tumor-induced CD11b+ Gr-1+ myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner. In: European Journal of Immunology. 2015 ; Vol. 45, No. 4. pp. 1148-1158.
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abstract = "Immunosuppressive CD11b+Gr-1+ myeloid-derived suppressor cells (MDSCs) accumulate in the livers of tumor-bearing (TB) mice. We studied hepatic MDSCs in two murine models of immune-mediated hepatitis. Unexpectedly, treatment of TB mice with Concanavalin A (Con A) or α-galactosylceramide resulted in increased alanine aminotransferase (ALT) and aspartate aminotransferase (AST) serum levels in comparison to tumor-free mice. Adoptive transfer of hepatic MDSCs into na{\"i}ve mice exacerbated Con A induced liver damage. Hepatic CD11b+Gr-1+ cells revealed a polarized proinflammatory gene signature after Con A treatment. An IFN-γ-dependent upregulation of CD40 on hepatic CD11b+Gr-1+ cells along with an upregulation of CD80, CD86, and CD1d after Con A treatment was observed. Con A treatment resulted in a loss of suppressor function by tumor-induced CD11b+Gr-1+ MDSCs as well as enhanced reactive oxygen species (ROS)-mediated hepatotoxicity. CD40 knockdown in hepatic MDSCs led to increased arginase activity upon Con A treatment and lower ALT/AST serum levels. Finally, blockade of arginase activity in Cd40-/- tumor-induced myeloid cells resulted in exacerbation of hepatitis and increased ROS production in vivo. Our findings indicate that in a setting of acute hepatitis, tumor-induced hepatic MDSCs act as proinflammatory immune effector cells capable of killing hepatocytes in a CD40-dependent manner.",
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