Nrf2 Mediated Metabolic Reprogramming Of Tolerogenic Dendritic Cells Is Protective Against Aplastic Anemia

Abstract Aplastic anemia (AA) is a rare autoimmunity characterized by suppression of bone marrow (BM) function resulting in progressive pancytopenia. BM transplants or immunosuppressive therapies remain the major treatment choices with limited benefit and significant side effects. Here we report for the first time the therapeutic utility of Nrf2 induced metabolically reprogrammed tolerogenic dendritic cells (TolDCs) in AA treatment. First, CDDO-DFPA-induced Nrf2 activation resulted in a TolDC phenotype as evidenced by induction of IL-4, IL-10, and TGF-b and suppression of TNFa, IFN-g, and IL-12 levels in Nrf2+/+but not in Nrf2−/− DCs. Cellular metabolism holds the key to determining DC immunogenic or tolerogenic cell fate. We observed the similar pattern of oxidative phosphorylation (OXPHOS) and glycolysis in immature and LPS-induced (matured) Nrf2+/+ and Nrf2−/− DCs. However, only Nrf2+/+DCs partially restored OXPHOS and reduced glycolysis during CDDO-DFPA-induced Nrf2 activation. We also 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. Besides, Nrf2−/−DCs demonstrated higher antigen-specific CD4 T cell proliferation. Lastly, administration of TolDCs improved hematopoiesis and survival rate in AA murine model, with fewer Th17 and more Treg cells. Concomitantly, AA patient BM biopsies displayed higher DCs, T cells, and iNOS expression accompanied with lower Nrf2 and HO-1 expression compared to normal subjects. These results provide a new insight into therapeutic utility of metabolically reprogramed TolDCs by CDDO-DFPA induced Nrf2 signaling in treatment of AA.