Nrf2 activation by sulforaphane restores the age-related decrease of T_H1 immunity: Role of dendritic cells

Background

The decrease in cellular immunity with aging is of considerable public health importance. Recent studies suggest that the redox equilibrium of dendritic cells (DCs) is a key factor in maintaining protective cellular immunity and that a disturbance of this homeostatic mechanism could contribute to immune senescence.

Objectives

We sought (1) to elucidate the role of DC redox equilibrium in the decrease of contact hypersensitivity (CHS) and T_H1 immunity during aging and (2) to determine how restoration of glutathione (GSH) levels by the Nrf2-mediated antioxidant defense pathway affects this decrease.

Methods

We assessed the effect of Nrf2 deficiency and boosting of GSH levels by the Nrf2 agonist sulforaphane or the thiol precursor N-acetyl cysteine (NAC) on the CHS response to contact antigens in old mice. We studied the effect of SFN and NAC on restoring T_H1 immunity by treating DCs ex vivo before adoptive transfer and in vivo challenge.

Results

Aging was associated with a decreased CHS response that was accentuated by Nrf2 deficiency. Systemic SFN treatment reversed this decrease through Nrf2-mediated antioxidant enzyme expression and GSH synthesis. Adoptive transfer of DCs from old animals induced a weakened CHS response in recipient animals. Treatment of DCs from old animals with SFN or NAC ex vivo restored the in vivo challenge response.

Conclusion

SFN and NAC upregulate T_H1 immunity in aging through a restoration of redox equilibrium.

Key words: Aging, redox equilibrium, cellular immunity, dendritic cells, Nrf2, glutathione, N-acetyl cysteine, sulforaphane

Abbreviations used: APC, Antigen-presenting cell, ARE, Antioxidant response element, BM-DC, Bone marrow–derived dendritic cell, CHS, Contact hypersensitivity, DC, Dendritic cell, DNBS, 2,4-Dinitrobenzene sulfonic acid, DNFB, 2,4-Dinitro-1-fluorobenzene, γ-GCL, γ-Glutamylcysteine ligase, γ-GCLR, γ-GCL regulatory subunit, GPx, Glutathione peroxidase, GSH, Glutathione, GSSG, Oxidized GSH, LC, Langerhans cell, MBB, Monobromobimane, NAC, N-acetyl cysteine, NQO1, Reduced nicotinamide adenine dinucleotide phosphate–quinone oxidoreductase, OXA, Oxazolone, p2E, Phase II enzyme, ROS, Reactive oxygen species, SFN, Sulforaphane