Comprising approximately 5-10 % of the circulating leukocyte pool, monocytes are a heterogeneous population of immune cells, which based on the differential surface expression of CD14 and the Fc receptor CD16 are categorised into one of three distinct subsets, namely classical (CD14++16-), intermediate (CD14++16+) and nonclassical (CD14+16++) [53]. Whilst age has no effect upon the frequency or absolute number of monocytes [54, 55], the composition of the monocyte pool is markedly different in older adults, who present with an increased frequency of non-classical and intermediate monocytes, and fewer classical monocytes when compared to their younger counterparts [55-57].

Providing frontline protection against viruses, bacteria and transformed cells, monocytes and macrophages are equipped with an array of anti-microbial mechanisms, which include chemotaxis, ROS generation, phagocytosis and antigen presentation. The results of rodent and human-based studies that have examined the impact of age on these functions are summarised in Fig. 1.1. In terms of macrophage function, conflicting observations are often reported, the result primarily of inter-study differences in such aspects of experimental design as the type of mouse strain, the source of tissue macrophages and the definition of “young” and “aged” mice.

The extent to which ageing impacts upon cytokine/chemokine generation by monocytes/macrophages has been the subject of considerable interest from immune gerontologists. Pathogen recognition by monocytes and macrophages is achieved primarily through their expression of toll like receptors (TLRs), a family of endosomal

Summary of age-related changes in monocyte and macrophage function. Italicfont indicates results obtained from rodent-based studies

Fig. 1.1 Summary of age-related changes in monocyte and macrophage function. Italicfont indicates results obtained from rodent-based studies

and surface residing receptors that recognise structurally conserved molecules shared by viruses, bacteria and fungi [58]. In the most extensive study to date that have investigated the effect of age on TLR-induced cytokine production, van Duin et al. measured intracellular IL-6 and TNF-a levels in monocytes isolated from young and older adults following TLR1/2, TLR2/6, TLR4, TLR5, TLR7 and/or TLR8 stimulation [59]. After controlling for a range of potential confounding factors such as medication, gender and vaccination history, the group reported a significant age-related reduction in TLR1/2-induced IL-6 and TNF-a synthesis [59]. Subsequent studies have confirmed this observation and demonstrated the aberration in TLR1/2-induced IL-6 production is a feature of all monocyte subsets [57]. In contrast to the impaired response to TLR1/2 stimulation, monocytes from older adults generate significantly greater amounts of TNF-a and IL-8 upon TLR4 or TLR5 stimulation respectively when compared to those from their younger counterparts [54, 56]. Whilst heightened responses of intermediate and non-classical monocytes drive the age-related enhancement in TLR4-induced TNF-a production [56], it is currently unknown which monocyte subset(s) is responsible for the increase in IL-8 synthesis following TLR5 stimulation. However, reports of an age-associated increase in TLR5 expression and signalling capacity provides a potential mechanistic explanation for the enhanced functional response of monocytes from older adults to TLR5 stimulation [54].

Based on the abovementioned age-related elevation in TLR5-induced cytokine production, immunologists are currently investigating whether manipulation of this signalling pathway could enhance the immune response elicited by older adults in times of infectious challenge. Early results are promising, with studies demonstrating a potential role for flagellin, the ligand for TLR5, as a vaccine adjuvant. In a model of Streptococcus pneumonaie infection, Lim and co-workers reported a 60 % increase in the survival rates of aged mice that received a combined pneumococcal surface protein A (PspA)-flagellin vaccine when compared to those mice vaccinated with PspA alone [60]. This increased survival rate was associated with significantly elevated levels of PspA-specific antibodies, suggesting that through activation of TLR5, robust immune responses can be generated in the aged host [60]. A similar approach has also proven successful in older adults, with a recombinant hemagglutinin influenza-flagellin fusion vaccine inducing seroconversion and seroprotection rates of 75 % and 98 % respectively in adults aged >65 years [61]. Interestingly, monocyte responsiveness in vitro to TLR stimulation is highly associated with vaccination responses. In a cohort of 162 young (21-30 years) and older (>65 years) subjects, an age-related reduction in TLR-induced up-regulation of the costimulatory molecule CD80 on the surface of monocytes was reported [62]. As subsequent analysis revealed an increased frequency of CD80+ monocytes post TLR stimulation was associated with an increased antibody response to influenza vaccination, prior assessment of monocyte reactivity to TLR stimulation may identify older adults unlikely to respond to vaccination [62].

To gain an insight into the mechanism(s) underlying the age-associated reduction in TLR-induced cytokine production, several groups have investigated the impact of age on the expression and/or signalling capacity of surface residing TLRs. Whilst TLR2 expression is comparable on monocytes from young and older adults [54, 57, 59], a significant age-related decline in TLR1 and TLR4 expression has been reported, which in the case of TLR1 is associated with reduced phosphorylation of the mitogen activated protein kinase (MAPK), extracellular signal-regulated kinase 1/2 (ERK 1/2) post TLR1/2 stimulation [57, 59]. On this theme of intracellular signalling, Olivieri et al. recently outlined how microRNAs (miRNAs) may be contributing to the dysregulation in TLR-induced cytokine production with age [63]. A family of short single-stranded RNA molecules that regulate gene expression, age-related changes in the levels of specific miRNAs may influence TLR- induced signalling by modulating the activity and/or expression of adaptor molecules and kinases central to TLR signal transduction [63].

Akin to monocytes, TLR-induced cytokine production by macrophages is significantly reduced with age. Following TLR1/2, TLR2/6, TLR3, TLR4, TLR5 and/or TLR9 stimulation, splenic, alveolar and peritoneal macrophages from aged mice secrete significantly less TNF-a, IL-6, IL-1p or IL-12 when compared to macrophages from their younger counterparts [64-68]. Mechanistically, this age-related aberration in TLR-induced pro-inflammatory cytokine production has been assigned to reduced expression of TLRs, increased production of the anti-inflammatory cytokine IL-10, altered expression of miRNAs and defective MAPK and protein kinase C signalling [64-69]. In one of the few studies investigating the impact of age on human macrophage function, Agius and colleagues assessed TNF-a production by skin macrophages in a model of cutaneous delayed type hypersensitivity and reported a significantly reduced percentage of TNF-a+ macrophages in skin biopsies taken from older adults [70]. Interestingly, rather than a defect intrinsic to macrophages, the group attributed this reduced production of TNF-a to an increased proportion in the skin of older adults of regulatory T cells, an immune cell subset that suppresses TNF-a production by macrophages [70]. Indeed, when macrophages isolated from the skin of young and older adults were subjected to TLR stimulation in vitro, no age-related differences in TNF-a production were observed [70].

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