Age-dependent dysregulation of innate immunity

Abstract

As we age, the innate immune system becomes dysregulated and is characterized by persistent inflammatory responses that involve multiple immune and non-immune cell types and that vary depending on the cell activation state and tissue context. This ageing-associated basal inflammation, particularly in humans, is thought to be induced by several factors, including the reactivation of latent viral infections and the release of endogenous damage-associated ligands of pattern recognition receptors (PRRs). Innate immune cell functions that are required to respond to pathogens or vaccines, such as cell migration and PRR signalling, are also impaired in aged individuals. This immune dysregulation may affect conditions associated with chronic inflammation, such as atherosclerosis and Alzheimer's disease.

Figure 1. Organ-specific changes of the innate immune system associated with ageing and disease

The effects of aging in various organ systems are depicted. Diminished innate immune responses are found in some cases—such as in skin, where a decrease in TNF production by macrophages results in decreased endothelial cell activation and diminished DTH responses. In addition, studies in mice have linked diminished neutrophil recruitment to impaired wound healing. Decreased NK cell function and induced NLRP3 function in response to influenza virus influence infection in the lung. However, there are also examples of dysregulated inflammatory responses found in aging. For example, in the lung following burn injury in a murine model, there is increased neutrophil inflammation. In the liver there is experimental data showing that NKT cells exhibit exaggerated inflammatory responses that contribute to immune pathology during viral infection or to TLR activators. In the brain, TLR and inflammasome signalling are elevated with aging, and are associated with microglial activation. Signalling via the NLRP3 inflammasome contributes to increased age-associated inflammation in adipose tissue as well. Finally, within the vasculature, increased basal IL-6 production by vascular smooth muscle cells has been found in aged rodents and non-human primates and may provide a potential explanation for the increased prevalence of atherosclerosis with aging.

Figure 2. Effects of ageing on innate immune PRR signalling

TLR and NLRP3 signalling pathways are depicted, with NF-κB-dependent pathways indicated in blue and type I interferon pathways indicated in red. With aging, elevated levels of PRR ligands (DAMPs) arising from cell damage, necrosis, lipotoxicity or other causes contribute to an elevated pro-inflammatory state, as manifested by increased basal levels of proinflammatory cytokines that may result in part from both TLR and NLRP3 signalling. Such basal activation may restrict responsiveness to new pathogens or vaccines, resulting in innate immune failure and impaired adaptive immune responses. Changes in protein expression for TLR1 and TLR5 in humans are indicated; results in mice suggest either a widespread decrease in TLR gene expression, or preserved expression with changes in intracellular signaling proteins (e.g. p38 MAP kinase). Abbreviations: TLR—Toll-like Receptor; IFNAR—type I Interferon receptor; MyD88—myeloid differentiation primary response 88; TRIF—Toll/IL1 receptor domain-containing adapter-inducing interferon-β; TRAM—TRIF-related adaptor molecule; IRF3—interferon regulatory factor 3; IRF7—interferon regulatory factor 7; NLRP3—NOD-like receptor family, pyrin domain containing 3; ASC—Apoptosis-associated speck-like protein containing a CARD.