Mechanisms of allergy and clinical immunology
Nrf2 activation by sulforaphane restores the age-related decrease of TH1 immunity: Role of dendritic cells

https://doi.org/10.1016/j.jaci.2008.01.016Get rights and content

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 TH1 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 TH1 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 TH1 immunity in aging through a restoration of redox equilibrium.

Section snippets

Mice

Young (2-4 months) and old (19-22 months) female C57BL/6 (B6) mice were obtained from the Jackson Laboratory and the National Institute of Aging colony (Bethesda, Md), respectively. Nrf2+/+ and nrf2−/− mice, which were initially obtained from Dr Y. Kan,14 were backcrossed onto a C57BL/6 background for 7 generations.

Reagents

For more information, see the Online Repository at www.jacionline.org.

CHS testing with contact-sensitizing agents

Oxazalone (OXA; 3%), dissolved in 100% ethanol, was applied on the shaved mouse abdomen on day 0. Control

SFN restores the age-related decrease in the CHS and TH1 immunity

We have previously shown that aging leads to a decrease of the CHS to contact antigens placed on the skin.13 Although a number of mechanisms might explain the increase in oxidant stress during aging, it is important to consider the role of the Nrf2 pathway in the response outcome. Recent studies indicate that SFN significantly activates Nrf2-mediated p2E gene expression that is absent in Nrf2-deficient animals.8 SFN administration can therefore be used to study the effect of the Nrf2 pathway on

Discussion

In this study we demonstrate that manipulation of the Nrf2 pathway affects CHS and TH1-mediated immune responses in old mice. Similar observations were made by using an adoptive transfer approach that uses ex vivo modification of DC redox status to study CHS responses in vivo. This is compatible with the growing recognition of the importance of the Nrf2 pathway on innate immunity.10 We demonstrate that the oral administration of a potent Nrf2 agonist, SFN, reverses the decrease of CHS responses

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    Supported by US Public Health Science support from the National Institute of Ageing (RO1 AG14992), the UCLA Claude D. Pepper Older Americans Independence Center (5P30 AG028748), and the National Institute of Allergy and Infectious Diseases–funded UCLA Asthma and Allergic Disease Clinical Research Center (U19 AI070453).

    Disclosure of potential conflict of interest: The authors have declared that they have no conflict of interest.

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