title: Tumor-induced CD11b(+) Gr-1(+) myeloid-derived suppressor cells exacerbate immune-mediated hepatitis in mice in a CD40-dependent manner.
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.
authors.affiliation: Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA; Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
authors.forename: Tamar
authors.initials: T
authors.lastname: Kapanadze
authors.forename: José
authors.initials: J
authors.lastname: Medina-Echeverz
authors.forename: Jaba
authors.initials: J
authors.lastname: Gamrekelashvili
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Weiss
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
authors.forename: Veena
authors.initials: V
authors.lastname: Kapoor
authors.forename: Nga
authors.initials: N
authors.lastname: Hawk
authors.forename: Masaki
authors.initials: M
authors.lastname: Terabe
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Ena
authors.initials: E
authors.lastname: Wang
authors.forename: Francesco M
authors.initials: FM
authors.lastname: Marincola
authors.forename: Firouzeh
authors.initials: F
authors.lastname: Korangy
authors.forename: Tim F
authors.initials: TF
authors.lastname: Greten
mesh_terms: D019264:Adoptive Transfer; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D055610:Antigens, CD1d / Q000096:biosynthesis; D001119:Arginase / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism; D001219:Aspartate Aminotransferases / Q000097:blood; D018122:B7-1 Antigen / Q000096:biosynthesis; D051940:B7-2 Antigen / Q000096:biosynthesis; D039481:CD11b Antigen / Q000378:metabolism; D019013:CD40 Antigens / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003208:Concanavalin A / Q000494:pharmacology; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology; D006505:Hepatitis / Q000235:genetics / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000166:cytology / Q000293:injuries; D008113:Liver Neoplasms / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008934:Mitogens / Q000494:pharmacology; D022423:Myeloid Cells / Q000276:immunology* / Q000637:transplantation; D017382:Reactive Oxygen Species / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism
chemical_list: D055610:Antigens, CD1d; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D039481:CD11b Antigen; C584692:CD1d antigen, mouse; D019013:CD40 Antigens; C497965:Cd86 protein, mouse; D005699:Galactosylceramides; C503133:Gr-1 protein, mouse; D008934:Mitogens; D017382:Reactive Oxygen Species; D019707:Receptors, Chemokine; C493154:alpha-galactosylceramide; D003208:Concanavalin A; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D001119:Arginase
keywords: CD40; Concanavalin A; Immune-mediated hepatitis; Myeloid-derived suppressor cells; Reactive oxygen species; α-Galactosylceramide