Nrf2-mediated metabolic reprogramming of tolerogenic dendritic cells is protective against aplastic anemia

J Autoimmun. 2018 Nov:94:33-44. doi: 10.1016/j.jaut.2018.07.005. Epub 2018 Jul 17.

Abstract

Aplastic anemia (AA) is a rare disease characterized by immune-mediated suppression of bone marrow (BM) function resulting in progressive pancytopenia. Stem cell transplant and immunosuppressive therapies remain the major treatment choices for AA patients with limited benefit and undesired side effects. Here, we report for the first time the therapeutic utility of Nrf2-induced metabolically reprogrammed tolerogenic dendritic cells (TolDCs) in the suppression of AA in mice. CDDO-DFPA-induced Nrf2 activation resulted in a TolDC phenotype as evidenced by induction of IL-4, IL-10, and TGF-β and suppression of TNFα, IFN-γ, and IL-12 levels in Nrf2+/+ but not Nrf2-/- DCs. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. Although immature and LPS-induced (mature) Nrf2+/+ and Nrf2-/- DCs exhibited similar patterns of oxidative phosphorylation (OXPHOS) and glycolysis, only Nrf2+/+ DCs partially restored OXPHOS and reduced glycolysis during CDDO-DFPA-induced Nrf2 activation. These results were further confirmed by altered glucose uptake and lactate production. We observed significantly enhanced HO-1 and reduced iNOS/NO production in Nrf2+/+ compared to Nrf2-/- DCs, suggesting Nrf2-dependent TolDC induction is linked to suppression of the inhibitory effect of NO on OXPHOS. Furthermore, Nrf2-/- DCs demonstrated higher antigen-specific T cell proliferation. Lastly, TolDC administration improved hematopoiesis and survival in AA murine model, with decreased Th17 and increased Treg cells. Concomitantly, immunohistochemical analysis of AA patient BM biopsies displayed higher DCs, T cells, and iNOS expression accompanied with lower Nrf2 and HO-1 expression when compared to normal subjects. These results provide new insight into the therapeutic utility of metabolically reprogrammed TolDCs by CDDO-DFPA induced Nrf2 signaling in the treatment of AA.

Keywords: Aplastic anemia; Bone marrow failure; Metabolism; Nrf2; Tolerogenic dendritic cell; Triterpenoid.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adolescent
  • Anemia, Aplastic / genetics
  • Anemia, Aplastic / immunology
  • Anemia, Aplastic / pathology
  • Anemia, Aplastic / therapy*
  • Animals
  • Cellular Reprogramming / immunology*
  • Child
  • Child, Preschool
  • Cytokines / genetics
  • Cytokines / immunology
  • Dendritic Cells / cytology
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology*
  • Dendritic Cells / transplantation
  • Disease Models, Animal
  • Gene Expression Regulation
  • Glycolysis / drug effects
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / immunology
  • Humans
  • Immune Tolerance / drug effects*
  • Lymphocyte Activation / drug effects
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-E2-Related Factor 2 / deficiency
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / immunology*
  • Nitric Oxide Synthase Type II / genetics
  • Nitric Oxide Synthase Type II / immunology
  • Oleanolic Acid / analogs & derivatives*
  • Oleanolic Acid / chemical synthesis
  • Oleanolic Acid / pharmacology
  • Oxidative Phosphorylation / drug effects
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / pathology
  • Th17 Cells / drug effects
  • Th17 Cells / immunology
  • Th17 Cells / pathology
  • Young Adult

Substances

  • 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
  • Cytokines
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Oleanolic Acid
  • NOS2 protein, human
  • Nitric Oxide Synthase Type II
  • HMOX1 protein, human
  • Heme Oxygenase-1