title: Cyclic adenosine monophosphate-responsive element modulator alpha overexpression impairs function of hepatic myeloid-derived suppressor cells and aggravates immune-mediated hepatitis in mice.
abstract: Molecular factors driving immune-mediated inflammation in the liver are incompletely understood. The transcription factor, cyclic adenosine monophosphate-responsive element modulator alpha (CREMα) can endorse differentiation of T lymphocytes toward T-helper (Th)17 cells, thereby promoting autoimmunity in systemic lupus erythematosus or lung inflammation. To investigate the role of CREMα in liver disease, we subjected transgenic (Tg) mice overexpressing CREMα under control of the CD2 promoter (cremtg mice), which restrains expression mainly to lymphocytes (T, natural killer [NK], and NKT cells), to acute and chronic liver injury models. Already in steady state, Tg CREMα overexpression broadly reduced hepatic immune cell numbers by decreasing their viability, but did not affect immune cell migration or the fibrogenic response to chronic liver injury. Strikingly, cremtg mice developed more severe immune-mediated hepatitis with a higher mortality rate, compared to wild-type (wt) mice, upon concanavalin A (ConA) administration. Unlike in T cells from spleen, CREMα overexpression did not induce a predominant Th17 response in intrahepatic T cells, given that hepatic cremtg CD4+ T cells expressed less interleukin (IL)-17 than wt T cells. Reconstitution of Rag1-/- mice with Crem-/- T cells did not ameliorate ConA hepatitis. Overexpression of CREMα did not influence NK and NKT-cell effector functions either. Interestingly, a subset of monocytic myeloid-derived suppressor cells (MDSCs) also expressed CD2 and CREMα. Cremtg MDSCs isolated from liver expressed reduced inducible nitric oxide synthase and arginase 1 and displayed a reduced T-cell suppressive activity. The adoptive transfer of wt MDSCs was capable of reducing the fulminant immune-mediated liver damage in cremtg mice to wt level.
  
  
  CONCLUSIONS
  These results suggest compartmental differences of T cell activation pathways between liver and other organs in autoimmunity and define a functional role of CREMα in hepatic monocytic MDSCs for the pathogenesis of immune-mediated liver disease.
authors.affiliation: Department of Medicine III, RWTH University-Hospital Aachen, Aachen, Germany.
authors.forename: Linda
authors.initials: L
authors.lastname: Hammerich
authors.forename: Klaudia Theresa
authors.initials: KT
authors.lastname: Warzecha
authors.forename: Martina
authors.initials: M
authors.lastname: Stefkova
authors.forename: Matthias
authors.initials: M
authors.lastname: Bartneck
authors.forename: Kim
authors.initials: K
authors.lastname: Ohl
authors.forename: Nikolaus
authors.initials: N
authors.lastname: Gassler
authors.forename: Tom
authors.initials: T
authors.lastname: Luedde
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.forename: Klaus
authors.initials: K
authors.lastname: Tenbrock
authors.forename: Frank
authors.initials: F
authors.lastname: Tacke
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018801:CD2 Antigens / Q000032:analysis; D002454:Cell Differentiation; D003208:Concanavalin A; D051786:Cyclic AMP Response Element Modulator / Q000502:physiology*; D019693:Hepatitis, Autoimmune / Q000209:etiology*; D008099:Liver / Q000276:immunology*; D008106:Liver Cirrhosis, Experimental / Q000209:etiology; D051379:Mice; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000502:physiology*; D013601:T-Lymphocytes / Q000276:immunology; D058504:Th17 Cells / Q000502:physiology
chemical_list: D018801:CD2 Antigens; D003208:Concanavalin A; D051786:Cyclic AMP Response Element Modulator