Acute Stress Reduces Wound-Induced Activation of Microbicidal Potential of Ex Vivo Isolated Human Monocyte-Derived Macrophages

Abstract

BackgroundPsychological stress delays wound healing but the precise underlying mechanisms are unclear. Macrophages play an important role in wound healing, in particular by killing microbes. We hypothesized that (a) acute psychological stress reduces wound-induced activation of microbicidal potential of human monocyte-derived macrophages (HMDM), and (b) that these reductions are modulated by stress hormone release.MethodsFourty-one healthy men (mean age 35±13 years) were randomly assigned to either a stress or stress-control group. While the stress group underwent a standardized short-term psychological stress task after catheter-induced wound infliction, stress-controls did not. Catheter insertion was controlled. Assessing the microbicidal potential, we investigated PMA-activated superoxide anion production by HMDM immediately before and 1, 10 and 60 min after stress/rest. Moreover, plasma norepinephrine and epinephrine and salivary cortisol were repeatedly measured. In subsequent in vitro studies, whole blood was incubated with norepinephrine in the presence or absence of phentolamine (norepinephrine blocker) before assessing HMDM microbicidal potential.ResultsCompared with stress-controls, HMDM of the stressed subjects displayed decreased superoxide anion-responses after stress (p’s <.05). Higher plasma norepinephrine levels statistically mediated lower amounts of superoxide anion-responses (indirect effect 95% CI: 4.14–44.72). Norepinephrine-treated HMDM showed reduced superoxide anion-production (p<.001). This effect was blocked by prior incubation with phentolamine.ConclusionsOur results suggest that acute psychological stress reduces wound-induced activation of microbicidal potential of HMDM and that this reduction is mediated by norepinephrine. This might have implications for stress-induced impairment in wound healing.

Acute Wounding Alters the Beta2-Adrenergic Signaling and Catecholamine Synthetic Pathways in Keratinocytes

“…Skin tissue harvested in the absence of injected epinephrine, and within 30 minutes of surgical injury, was processed for catecholamine analysis. Levels range from those reported in nonstressed muscle (20 pg mg À 1 , (Ohkuwa et al, 2005)) to levels that approximate those found in human serum (B700 ng ml À 1 , (Kuebler et al, 2013)). Thus, it is clear that the wound microenvironment is one wherein norepinephrine is present, and levels may vary widely.…”

“…However, the role of systemic elevation of norepinephrine is less clear. Although depletion of systemic norepinephrine impairs healing (Gosain et al, 2006), acute increases in norepinephrine could impair healing by decreasing macrophage efficiency in generating microbicidal oxidizing agents (Kuebler et al, 2013). The differences in the magnitude of the systemic elevation and the persistence of this elevation may explain the discrepancy, and future studies will be needed to determine the effects of stress levels of systemic norepinephrine.…”

Stress-induced modulation of NF-κB activation, inflammation-associated gene expression, and cytokine levels in blood of healthy men

“…The sampling interval for every inflammatory measure 133 was chosen based on previous stress studies and in part further 134 clarified by kinetic testing. Our main hypotheses were that (1) 135 acute psychosocial stress induces rapid increases in NF-jB DNA 136 binding activity, as well as delayed increases in both mRNA and 137 plasma levels of the pro-inflammatory cytokines IL-1ß and IL- 6,138 and that (2) This study has been conducted within a project assessing the 145 stress reactivity of immune measures (Kuebler et al, 2013) Participants of the stress and control group reported to the lab-167 oratory by 10 a.m. and had to abstain from extensive physical exer-168 cise, alcohol, and caffeinated beverages during the previous 24 h. 169 Participants were given calorically standardized food with compa-170 rable amounts of macro-nutritional composition (i.e. fat, protein, 171 and carbohydrate) and an indwelling venous catheter was inserted.…”

Anticipatory cognitive stress appraisal modulates suppression of wound‐induced macrophage activation by acute psychosocial stress

“…The objective of the current study was to investigate in a secondary analysis of our previous study (Kuebler, Wirtz et al., ) whether anticipatory cognitive stress appraisal modulates the observed wound‐induced activation of macrophage microbicidal potential in acutely stressed (stress wound group) compared to nonstressed men (nonstress wound group). To preactivate circulating monocytes as precursors of later M1 macrophages in vivo, we inserted a venous catheter long enough to supposedly initiate wound‐healing processes (Kuebler, Ehlert et al., ; Kuebler, Wirtz et al., ). For psychosocial stress induction, we used the Trier Social Stress Test (TSST), which evokes profound psychological and physiological stress responses in a highly standardized and reliable manner (Dickerson & Kemeny, ; Kirschbaum, Pirke, & Hellhammer, ).…”

“…We recently found that wound‐induced activation of microbicidal potential (i.e., superoxide anion production) of human macrophages is suppressed by acute psychosocial stress (Kuebler, Wirtz, Sakai, Stemmer, & Ehlert, ). Macrophages are tissue‐resident immune cells that are derived from blood monocytes.…”