Aging Impairs IFN Regulatory Factor 7 Up-Regulation in Plasmacytoid Dendritic Cells during TLR9 Activation

Abstract

Plasmacytoid dendritic cells (pDCs) are innate sensors that produce IFN-α 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-α 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-α 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.

Impaired secretion of interferons by dendritic cells from aged subjects to influenza

“…Decline in IFN secretion by pDCs in aged subjects has been demonstrated to be due to defect in signaling mechanisms that result in impaired phosphorylation of Interferon Regulatory Factor-7 (IRF-7) (Sridharan et al 2010;Stout-Delgado et al 2008). More recently, Qian et al (2011) have reported decreased IFN-I secretion in monocyte derived DCs from older donors in response to West Nile virus due to decreased induction of STAT-1, IRF-7 and IRF-1.…”

“…Numerous studies have reported a decrease secretion of IFN-α by aged pDCs, which are the most potent IFN producing cells (Sridharan et al 2010;Stout-Delgado et al 2008;Diebold et al 2003;Jing et al 2009). Besides pDCs, the mDCs subset of DCs is also capable of producing robust amount of IFNs in response to viral infection (Katashiba et al 2011;Diebold et al 2003).…”

“…They produce copious amounts of IFN-I very early in the infection. We (Sridharan et al 2010) and others (Canaday et al 2010;Jing et al 2009;Shodell and Siegal 2002;Stout-Delgado et al 2008;Qian et al 2011) have reported decreased production of IFNs by pDC population in the aged subjects. In addition to pDC, the myeloid dendritic cells (mDCs) subset is also capable of producing IFNs in response to viral infection.…”

The Innate Immune System and Aging: What is the Contribution to Immunosenescence ?

“…Several virus derived molecules such ssRNA or CpG were unable to elicit TLR7 or TLR9 activation [63,64]. It seems that the increased basal oxidative stress related to aging could be the underlying cause of the decreased upregulation of the interferon regulatory factors by TLRs [16,65] . There is still controversy around whether the TLRs response to stimulation is altered with aging in macrophages or mDCs.…”

“…• Chemotaxis decreased or no change [15,16,17] Free radical production decrease [15,16,17] Intracellular killing decreased [15,16,17] Rescue from apoptosis decreased [18] Intracellular signalling altered [14,19,20 Free radical production decrease [56] Intracellular killing decrease [56] Pro-inflammatory cytokine production increased [47,48,54,57] Intracellular signalling altered [29,47,48,49] Dendritic cells Phenotype no change or decrease [47,63,64] Subpopulations no change [63,64] Receptors number decrease or no change [29,65] Functions Phagocytosis decrease or no change [63,72,73] Antigen presentation decreased [63,72] Chemotaxis decreased [73] Intracellular killing decrease [63] Pro-inflammatory cytokine production increased [63,66,68] T cell priming altered [63,72] Cytokine production decreased or no change [84,88] T cell priming altered …”