Loss of transcription factor nuclear factor-erythroid 2 (NF-E2) p45-related factor-2 (Nrf2) leads to dysregulation of immune functions, redox homeostasis, and intracellular signaling in dendritic cells.
Dendritic cells (DCs) are critical mediators of immunity and immune tolerance by orchestrating multiple aspects of T cell activation and function. Immature DCs (iDCs) expressing low levels of co-stimulatory receptors are highly efficient at antigen capture but are poor activators of T cells. Maturation of DCs is associated with increased expression of co-stimulatory molecules. Co-stimulatory receptor gene expression is regulated by intracellular redox, NF-κB, and MAPK pathways and by histone deacetylase (HDAC) activity. The transcription factor, Nrf2, is important for maintaining intracellular glutathione (GSH) levels and redox homeostasis and has been implicated in modulating DC co-stimulatory receptor expression. It is unclear whether Nrf2 mediates this effect by GSH-dependent mechanisms and whether it influences DC signaling pathways. Using bone marrow-derived iDCs from Nrf2(+/+) and Nrf2(-/-) mice, we demonstrate that Nrf2(-/-) iDCs have lower basal GSH levels, enhanced co-stimulatory receptor expression, impaired phagocytic functions, and increased antigen-specific CD8 T cell stimulation capacity. Interestingly, lowering GSH levels in Nrf2(+/+) iDCs did not recapitulate the Nrf2(-/-) iDC phenotype. Loss of Nrf2 resulted in elevated basal levels of reactive oxygen species but did not affect basal NF-κB activity or p38 MAPK phosphorylation. Using pharmacological inhibitors, we demonstrate that enhanced co-stimulatory receptor phenotype of Nrf2(-/-) iDC does not require ERK activity but is dependent on HDAC activity, indicating a potential interaction between Nrf2 function and HDAC. These results suggest that Nrf2 activity is required to counter rises in intracellular reactive oxygen species and to regulate pathways that control DC co-stimulatory receptor expression.
Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom.
Han Xian Aw
HXA
Yeang
Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom.
Junnat M
JM
Hamdam
Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom.
Laith M A
LMA
Al-Huseini
Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom.
Swaminathan
S
Sethu
Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom.
Laiche
L
Djouhri
Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom.
Joanne
J
Walsh
Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom.
Neil
N
Kitteringham
Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom.
B Kevin
BK
Park
Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom. Electronic address: chrissy@liv.ac.uk.
Christopher E
CE
Goldring
Department of Pharmacology, Medical Research Council Centre for Drug Safety Science, University of Liverpool, Sherrington Buildings, Ashton Street, Liverpool L69 3GE, United Kingdom. Electronic address: Jean.Sathish@liv.ac.uk.
Jean G
JG
Sathish
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism*; D005978:Glutathione / Q000235:genetics / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism
D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; C495636:Nfe2l2 protein, mouse; D017382:Reactive Oxygen Species; D048051:p38 Mitogen-Activated Protein Kinases; D006655:Histone Deacetylases; D005978:Glutathione