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.

Contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions

“…Monocytes, which are innate immune cells, are known to be mediators of the inflammatory response and comprise at least three different subsets, based on their expression of CD14 (a pattern recognition receptor binding microorganism-derived lipopolysaccharide) and CD16 (a low affinity receptor for the Fc portion of immunoglobulins), namely classical, intermediate and non-classical monocytes. An age-related increase in frequencies of intermediate and nonclassical monocytes has been reported (de Pablo-Bernal et al, 2016;Hearps et al, 2012). Our results from the Berlin Aging Study II confirmed these findings, where we also found an agerelated increase in frequencies of intermediate and non-classical monocytes (unpublished results).…”

Permanent control of HIV-1 pathogenesis in exceptional elite controllers: a model of spontaneous cure

“…Plasma samples were collected in EDTA-lined tubes, and aliquoted and stored at −20 °C. The levels of high sensitivity C-reactive protein (hsCRP) and β2-microglobulin (β2M), D-dimer, IL-6 and sCD163 were performed as described 22 .…”

Cytomegalovirus serostatus, inflammation, and antibody response to influenza vaccination in older adults: The moderating effect of beta blockade

“…A well-controlled CMV infection is likely to have different effects than one that is poorly controlled and, indeed, in previous studies, CMV antibody titers correlated with peak antibody response after influenza vaccination where serostatus did not (den Elzen et al, 2011; Furman et al, 2015; Trzonkowski et al, 2003). CMV antibody titers also correlated with markers of immune activation (de Pablo-Bernal et al, 2015; Trzonkowski et al, 2003). The age of the archived samples in the present study (dating back to 2001) suggested that serostatus could be more reliably measured than antibody titer; however, future research should examine both CMV serostatus and titers.…”

“…The cytokine profile of senescent cells is more proinflammatory than non-senescent cells (Effros, 2012; Effros, Dagrarag, Spaulding, & Man, 2005). CMV antibody titers correlate with proinflammatory cytokines in serum, as well as monocyte activation (de Pablo-Bernal et al, 2015; Trzonkowski et al, 2003). Ultimately, enhanced “inflammaging” due to CMV could increase risk for multiple health problems of older adulthood (Ershler & Keller, 2000; Frasca & Blomberg, 2016).…”