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Review
. 2012 Nov 16;37(5):771-83.
doi: 10.1016/j.immuni.2012.10.014.

Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly

Tobias R Kollmann  1 , Ofer Levy, Ruth R Montgomery, Stanislas Goriely
Affiliations
Review

Innate immune function by Toll-like receptors: distinct responses in newborns and the elderly

Tobias R Kollmann et al. Immunity. .

Abstract

Given the "inborn" nature of the innate immune system, it is surprising to find that innate immune function does in fact change with age. Similar patterns of distinct Toll-like-receptor-mediated immune responses come to light when one contrasts innate immune development at the beginning of life with that toward the end of life. Importantly, these developmental patterns of innate cytokine responses correlate with clinical patterns of susceptibility to disease: A heightened risk of suffering from excessive inflammation is often detected in prematurely born infants, disappears over the first few months of life, and reappears toward the end of life. In addition, risk periods for particular infections in early life reemerge in older adults. The near-mirror-image patterns that emerge in contrasts of early versus late innate immune ontogeny emphasize changes in host-environment interactions as the underlying molecular and teleologic drivers.

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Figures

Figure 1
Figure 1. Age-Dependent Changes in TLR-Induced Immune Regulatory Function
Early Life: (1) Cord blood of pre-term infants produces large amounts of the anti-inflammatory cytokine IL-10 but low amounts of proinflammatory cytokines. (2) Whole blood of term newborns produces large quantities of IL-6 and IL-23 after TLR stimulation; these cytokines are known to support Th17 cell differentiation. (3) TLR-mediated induction of type 1 IFN in pDCs is markedly reduced at birth but rapidly reaches adult-level function within a few weeks after birth. (4) Over the first few years of life, TLR-induced generation of proinflammatory cytokines such as TNF-a and IL-1b steadily increases in monocytes and cDCs. The gradual postnatal increase in the ability to produce TNF-a and IL-1b is paralleled by a slow decline of IL-10, IL-6, and IL-23. (5) TLR-mediated production of Th1-cell-supporting cytokines such as IL-12p70 reaches adult levels only after 2 years of age. Later Life: Chronic low-grade systemicinflammation (inflammaging) reflected by higher plasmatic levels of IL-6, TNF-a, and other innate cytokines; “unimpaired” older people instead express higher levels of IL-10 and lower levels of most other innate cytokines in response to whole-blood TLR stimulation.
Figure 2
Figure 2. Molecular Mechanisms Active Early in Life
NF-κB activation downstream of cell-surface TLRs in newborn monocytes occurs at least at adult levels, suggesting that age-dependent differences in NF-κB-dependent cytokine production must be the result of other pathways. For example, (1) higher levels of extracellular adenosine early in life, coupled with an elevated sensitivity of G protein-coupled adenosine receptors, leads to higher cytosolic concentrations of cAMP, which might produce a bias toward Th2 and against Th1 cell responses. (2) For endosomal TLRs, TLR8 signaling in newborn cells occurs at least at adult levels, leading to robust TNFα production. However, in cord-blood plasmacytoid DCs, (3) signals downstream of TLR7 or TLR9 leading to IRF7 phosphorylation and nuclear translocation are reduced, and production of type 1 IFN is thus impaired. Furthermore, although TRIF-dependent activation and nuclear translocation of IRF3 downstream of TLR3 or TLR4 occurs at adult levels in cord-blood-derived myeloid DCs, (4) IRF3 DNA-binding activity and association with CBP is decreased in newborn DCs as compared to adult DCs, providing a basis for (5) impaired neonatal IL-12p35 and IFN-β production.
Figure 3
Figure 3. Molecular Mechanisms Active Late in Life
(1) Reduced expression of most TLRs, except TLR5, leads to lower TLR responses in older adults. Older adults also display altered signaling downstream of TLRs. For example, they display (2) lower p38 signaling via TLR4 and (3) diminished induction of late-phase responses mediated by STAT1, IRF7, and IRF1. This, in turn, leads to (4) defective regulation of the type I IFN axis in DCs. Some differences in older adults are lineage specific: Monocytes demonstrate greater TLR5 expression and increased p38 signaling, whereas macrophages demonstrate impaired downregulation of TLR3 and elevated cytokine production. Furthermore, (5) an age-associated decrease of autophagy reduces clearance of damaged mitochondria, which elevates cellular ROS production and associated RLR signaling and inflammation, setting into motion a vicious cycle.
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