Monocyte Phenotype and Polyfunctionality Are Associated With Elevated Soluble Inflammatory Markers, Cytomegalovirus Infection, and Functional and Cognitive Decline in Elderly Adults

Abstract

Monocytes are mediators of the inflammatory response and include three subsets: classical, intermediate, and nonclassical. Little is known about the phenotypical and functional age-related changes in monocytes and their association with soluble inflammatory biomarkers, cytomegalovirus infection, and functional and mental decline. We assayed the activation ex vivo and the responsiveness to TLR2 and TLR4 agonists in vitro in the three subsets and assessed the intracellular production of IL1-alpha (α), IL1-beta (β), IL-6, IL-8, TNF-α, and IL-10 of elderly adults (median 83 [67-90] years old;n= 20) compared with young controls (median 35 [27-40] years old;n= 20). Ex vivo, the elderly adults showed a higher percentage of classical monocytes that expressed intracellular IL1-α (p= .001), IL1-β (p= .001), IL-6 (p= .002), and IL-8 (p= .007). Similar results were obtained both for the intermediate and nonclassical subsets and in vitro. Polyfunctionality was higher in the elderly adults. The functionality ex vivo was strongly associated with soluble inflammatory markers. The activation phenotype was independently associated with the anti-cytomegalovirus IgG levels and with functional and cognitive decline. These data demonstrate that monocytes are key cell candidates for the source of the high soluble inflammatory levels. Our findings suggest that cytomegalovirus infection might be a driving force in the activation of monocytes and is associated with the functional and cognitive decline.

Keywords: Aging; CMV; Cognitive; Inflammation; Mini-mental; Monocyte function.

Figure 1.

(A) Schematic diagram of the gating strategy of an elderly participant. Note that after LPS stimulation, despite the shedding of CD16, the nonclassical subset was gated. (B) Histogram representation of cytokine expression on classical monocytes without stimuli and with LPS stimulation. (C) Pie charts show classical monocytes with up to six functional responses to LPS stimulation. Statistically significant differences between the findings are shown. Pestle version 1.6.2 and Spice version 5.2 (M. Roederer, NIH, Bethesda, MD) were used.

Figure 2.

Correlations among the soluble biomarkers and monocyte function ex vivo in the elderly and young groups (n = 40). Heatmap representing negative (blue shading) and positive (red shading) associations between soluble inflammatory markers and single intracellular cytokine production in the three monocyte subsets. Spearman ρ correlation coefficient test was used. **p < .001. *p < .05.^Θ p < .1.

Figure 3.

(A and B) Graphical representation of the relationship between anti-cytomegalovirus titers and the percentage of monocytes expressing CD40 and CD62L. (C) Graphical representation of the association between Mini-Mental State Examination and the CD11b expression on classical monocytes in the elderly group. Spearman ρ correlation coefficient test was used.