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The Journal of Immunology, 2008, 181, 6747-6756
Copyright © 2008 by The American Association of Immunologists, Inc.
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Aging Impairs IFN Regulatory Factor 7 Up-Regulation in Plasmacytoid Dendritic Cells during TLR9 Activation1

Heather W. Stout-Delgado, Xin Yang, Wendy E. Walker, Bethany M. Tesar and Daniel R. Goldstein2

Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510

Plasmacytoid dendritic cells (pDCs) are innate sensors that produce IFN-{alpha} in response to viral infections. Determining how aging alters the cellular and molecular function of these cells may provide an explanation of increased susceptibility of older people to viral infections. Hence, we examined whether aging critically impairs pDC function during infection with HSV-2, a viral pathogen that activates TLR9. We found that impaired IFN-{alpha} production by aged murine pDCs led to impaired viral clearance with aging. Upon TLR9 activation, aged pDCs displayed defective up-regulation of IFN-regulatory factor 7, a key adaptor in the type I IFN pathway, as compared with younger counterparts. Aged pDCs had more oxidative stress, and reducing oxidative stress in aged pDCs partly recovered the age-induced IFN-{alpha} defect during TLR9 activation. In sum, aging impairs the type I IFN pathway in pDCs, and this alteration may contribute to the increased susceptibility of older people to certain viral infections.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported in part by National Institutes of Health Grants AG028082 and AG026772 (Paul B. Beeson Award in Aging Research) (to D.R.G.). H.W.S.-D. is supported by National Institutes of Health Grant T32AG019134. W.E.W. is supported by National Institutes of Health Grant 5T32HL007778.

2 Address correspondence and reprint requests to Dr. Daniel R. Goldstein, Department of Internal Medicine, 333 Cedar Street, 3 FMP, P.O. Box 208017, Yale University School of Medicine, New Haven, CT 06520. E-mail address: daniel.goldstein{at}yale.edu

3 Abbreviations used in this paper: DC, dendritic cell; AL, ad libitum; CR, calorie restriction; DHE, dihydroethidium; IRF, interferon regulatory factor; NAC, N-acetylcysteine; pDC, plasmacytoid DC; ROS, reactive oxygen species; DOTAP, 1,2-dioleoyl-3-(trimethyammonium)propane; IKK, I{kappa}B kinase; ODN, oligodeoxynucleotide; MCMV, murine CMV; IRAK, IL-1R-associated kinase.


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The JI 2008 181: 6677-6678. [Full Text]  





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