Dataset Information

Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults.

ABSTRACT:

Background

Recent experimental approaches have unraveled essential migratory and functional differences of monocyte subpopulations in mice. In order to possibly translate these findings into human physiology and pathophysiology, human monocyte subsets need to be carefully revisited in health and disease. In analogy to murine studies, we hypothesized that human monocyte subsets dynamically change during ageing, potentially influencing their functionality and contributing to immunosenescence.

Results

Circulating monocyte subsets, surface marker and chemokine receptor expression were analyzed in 181 healthy volunteers (median age 42, range 18-88). Unlike the unaffected total leukocyte or total monocyte counts, non-classical CD14+CD16+ monocytes significantly increased with age, but displayed reduced HLA-DR and CX(3)CR1 surface expression in the elderly. Classical CD14++CD16- monocyte counts did not vary dependent on age. Serum MCP-1 (CCL2), but not MIP1alpha (CCL3), MIP1beta (CCL4) or fractalkine (CX(3)CL1) concentrations increased with age. Monocyte-derived macrophages from old or young individuals did not differ with respect to cytokine release in vitro at steady state or upon LPS stimulation.

Conclusions

Our study demonstrates dynamic changes of circulating monocytes during ageing in humans. The expansion of the non-classical CD14+CD16+ subtype, alterations of surface protein and chemokine receptor expression as well as circulating monocyte-related chemokines possibly contribute to the preserved functionality of the monocyte pool throughout adulthood.

SUBMITTER: Seidler S

PROVIDER: S-EPMC2910032 | biostudies-literature | 2010 Jun

REPOSITORIES: biostudies-literature

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Publications

Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults.

Seidler Sebastian S Zimmermann Henning W HW Bartneck Matthias M Trautwein Christian C Tacke Frank F

BMC immunology 20100621

<h4>Background</h4>Recent experimental approaches have unraveled essential migratory and functional differences of monocyte subpopulations in mice. In order to possibly translate these findings into human physiology and pathophysiology, human monocyte subsets need to be carefully revisited in health and disease. In analogy to murine studies, we hypothesized that human monocyte subsets dynamically change during ageing, potentially influencing their functionality and contributing to immunosenescen ...[more]

PMID: 20565954

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Project description:BackgroundMonocytes are a heterogenous population of immune cells whose subsets and functions become substantially dysregulated with advanced age. Although much of our current understanding of the age-related changes in monocytes is derived from fasting blood samples, most people are predominately in the postprandial state during waking hours. As hormonal, metabolic, and immunological changes in response to the consumption of a meal are manifested in postprandial blood, it's unclear how age-dependent changes in peripheral monocytes at fasting are impacted by a dietary challenge.ObjectiveWe investigated the impact of age and meal consumption on circulating monocyte frequencies and subsets defined as classical (CD14 + CD16-), intermediate (CD14 + CD16 +), or non-classical (CD14dim CD16 +) in a cohort of 349 healthy adult volunteers grouped into categories based on their age: young adults (18-33 y, n = 123), middle adults (34-49 y, n = 115), and older adults (50-66 y, n = 111).ResultsFollowing 12-h fast total monocyte counts inversely correlated with subject age. Older adults had significantly fewer circulating monocytes along with elevated levels of TGs, cholesterol, glucose, IL-6, IL-8, TNF, neopterin, and CCL2 compared with young adults. Circulating monocyte pools in older adults consisted of smaller proportions of classical but larger proportions of intermediate and non-classical monocytes. Proportions of classical monocytes were inversely correlated with plasma TNF, IL-8, and neopterin while intermediate monocytes were positively correlated with plasma IL-6, TNF, and neopterin. Three hours after consuming a fat-containing meal postprandial monocyte counts increased in all age groups. Despite age-dependent differences in monocyte subsets at fasting, consumption of a meal induced similar changes in the proportions of classical and non-classical monocytes across age groups. Within the circulating postprandial monocyte pool, percentages of classical monocytes decreased while non-classical monocytes increased. However no change in precursory intermediate monocytes were detected. Our study confirms that ageing is associated with changes in monocyte frequencies and subsets and shows that consuming a fat-containing meal induces temporal changes in monocyte frequency and subsets independently of subject age.Clinical trialRegistered on ClincialTrials.gov (Identifier: NCT02367287).

Project description:Genome wide DNA methylation profiling of isolated monocyte samples from healthy Kenyan children, the same children during an episode of acute malaria, healthy Kenyan adults, and healthy adults from the United States. The Illumina Infinium MethylationEPIC BeadChip microarray was used to obtain DNA methylation profiles across approximately 860,000 CpGs in negatively selected monocyte samples. Samples included monocytes from 8 children from western Kenya obtained while healthy and matching samples from the same 8 Kenyan children obtained during an episode of acute uncomplicated Plasmodium falciparum malaria, 8 healthy malaria-immune adults from western Kenya, and 8 healthy malaria-naive adults from the US. Abstract -- Background: Age-related changes in adaptive and innate immune cells have been associated with a decline in effective immunity and chronic, low-grade inflammation. Epigenetic, transcriptional, and functional changes in monocytes occur with aging, though most studies to date have focused on differences between young adults and the elderly in populations with European ancestry; few data exist regarding changes that occur in circulating monocytes during the first few decades of life or in African populations. We analyzed DNA methylation profiles, cytokine production, and inflammatory gene expression profiles in monocytes from young adults and children from western Kenya. Results: We identified several hypo- and hyper-methylated CpG sites in monocytes from Kenyan young adults vs. children that replicated findings in the current literature of differential DNA methylation in monocytes from elderly persons vs. young adults across diverse populations. Differentially methylated CpG sites were also noted in gene regions important to inflammation and innate immune responses. Monocytes from Kenyan young adults vs. children displayed increased production of IL-8, IL-10, and IL-12p70 in response to TLR4 and TLR2/1 stimulation as well as distinct inflammatory gene expression profiles. Conclusions: These findings complement previous reports of age-related methylation changes in isolated monocytes and provide novel insights into the role of age-associated changes in innate immune functions.

Project description:BackgroundAltered monocyte NF-κB signaling is a possible cause of inflammaging and driver of aging, however, evidence from human aging studies is sparse. We assessed monocyte NF-κB signaling across different aging trajectories by comparing healthy older adults to older adults with a recent emergency department (ED) admission and to young adults.MethodsWe used data from: 52 older (≥65 years) Patients collected upon ED admission and at follow-up 30-days after discharge; 52 age- and sex-matched Older Controls without recent hospitalization; and 60 healthy Young Controls (20-35 years). Using flow cytometry, we assessed basal NF-κB phosphorylation (pNF-κB p65/RelA; Ser529) and induction of pNF-κB following stimulation with LPS or TNF-α in monocytes. We assessed frailty (FI-OutRef), physical and cognitive function, and plasma levels of IL-6, IL-18, TNF-α, and soluble urokinase plasminogen activator receptor.ResultsPatients at follow-up were frailer, had higher levels of inflammatory markers and decreased physical and cognitive function than Older Controls. Patients at follow-up had higher basal pNF-κB levels than Older Controls (median fluorescence intensity (MFI): 125, IQR: 105-153 vs. MFI: 80, IQR: 71-90, p < 0.0001), and reduced pNF-κB induction in response to LPS (mean pNF-κB MFI fold change calculated as the log10 ratio of LPS-stimulation to the PBS-control: 0.10, 95% CI: 0.08 to 0.12 vs. 0.13, 95% CI: 0.10 to 0.15, p = 0.05) and TNF-α stimulation (0.02, 95% CI: - 0.00 to 0.05 vs. 0.10, 95% CI: 0.08 to 0.12, p < 0.0001). Older Controls had higher levels of inflammatory markers than Young Controls, but basal pNF-κB MFI did not differ between Older and Young Controls (MFI: 81, IQR: 70-86; p = 0.72). Older Controls had reduced pNF-κB induction in response to LPS and TNF-α compared to Young Controls (LPS: 0.40, 95% CI: 0.35 to 0.44, p < 0.0001; and TNF-α: 0.33, 95% CI: 0.27 to 0.40, p < 0.0001). In Older Controls, basal pNF-κB MFI was associated with FI-OutRef (p = 0.02).ConclusionsIncreased basal pNF-κB activity in monocytes could be involved in the processes of frailty and accelerated aging. Furthermore, we show that monocyte NF-κB activation upon stimulation was impaired in frail older adults, which could result in reduced immune responses and vaccine effectiveness.

Project description:BackgroundExcessive alcohol intake is associated with adverse immune response-related effects, however, acute and chronic abuse differently modulate monocyte activation. In this study, we have evaluated the phenotypic and functional changes of monocytes in acutely intoxicated healthy volunteers (HV).MethodsTwenty-two HV consumed individually adjusted amounts of alcoholic beverages until reaching a blood alcohol level of 1‰ after 4h (T4). Peripheral blood was withdrawn before and 2h (T2), 4h (T4), 6h (T6), 24h (T24), and 48h (T48) after starting the experiment and stained for CD14, CD16 and TLR4. CD14brightCD16-, CD14brightCD16+ and CD14dimCD16+ monocyte subsets and their TLR4 expression were analyzed by flow cytometry. Inflammasome activation via caspase-1 in CD14+ monocytes was measured upon an ex vivo in vitro LPS stimulation. Systemic IL-1β and adhesion capacity of isolated CD14+ monocytes upon LPS stimulation were evaluated.ResultsThe percentage of CD14+ monocyte did not change following alcohol intoxication, whereas CD14brightCD16- monocyte subset significantly increased at T2 and T24, CD14brightCD16+ at T2, T4 and T6 and CD14dimCD16+ at T4 and T6. The relative fraction of TLR4 expressing CD14+ monocytes as well as the density of TLR4 surface presentation increased at T2 and decreased at T48 significantly. TLR4+CD14+ monocytes were significantly enhanced in all subsets at T2. TLR4 expression significantly decreased in CD14brightCD16- at T48, in CD14brightCD16+ at T24 and T48, increased in CD14dimCD16+ at T2. IL-1β release upon LPS stimulation decreased at T48, correlating with TLR4 receptor expression. Alcohol downregulated inflammasome activation following ex vivo in vitro stimulation with LPS between T2 and T48 vs. T0. The adhesion capacity of CD14+ monocytes decreased from T2 with significance at T4, T6 and T48. Following LPS administration, a significant reduction of adhesion was observed at T4 and T6.ConclusionsAlcohol intoxication immediately redistributes monocyte subsets toward the pro-inflammatory phenotype with their subsequent differentiation into the anti-inflammatory phenotype. This is paralleled by a significant functional depression, suggesting an alcohol-induced time-dependent hyporesponsiveness of monocytes to pathogenic triggers.

Dataset Information

Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults.

Background

Results

Conclusions

Publications

Age-dependent alterations of monocyte subsets and monocyte-related chemokine pathways in healthy adults.

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