Voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans

Abstract

Excessive or persistent proinflammatory cytokine production plays a central role in autoimmune diseases. Acute activation of the sympathetic nervous system attenuates the innate immune response. However, both the autonomic nervous system and innate immune system are regarded as systems that cannot be voluntarily influenced. Herein, we evaluated the effects of a training program on the autonomic nervous system and innate immune response. Healthy volunteers were randomized to either the intervention (n = 12) or control group (n = 12). Subjects in the intervention group were trained for 10 d in meditation (third eye meditation), breathing techniques (i.a., cyclic hyperventilation followed by breath retention), and exposure to cold (i.a., immersions in ice cold water). The control group was not trained. Subsequently, all subjects underwent experimental endotoxemia (i.v. administration of 2 ng/kg Escherichia coli endotoxin). In the intervention group, practicing the learned techniques resulted in intermittent respiratory alkalosis and hypoxia resulting in profoundly increased plasma epinephrine levels. In the intervention group, plasma levels of the anti-inflammatory cytokine IL-10 increased more rapidly after endotoxin administration, correlated strongly with preceding epinephrine levels, and were higher. Levels of proinflammatory mediators TNF-α, IL-6, and IL-8 were lower in the intervention group and correlated negatively with IL-10 levels. Finally, flu-like symptoms were lower in the intervention group. In conclusion, we demonstrate that voluntary activation of the sympathetic nervous system results in epinephrine release and subsequent suppression of the innate immune response in humans in vivo. These results could have important implications for the treatment of conditions associated with excessive or persistent inflammation, such as autoimmune diseases.

Keywords: LPS; cathecholamines; cortisol.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.

Cardiorespiratory parameters, temperature, and symptoms during experimental endotoxemia in control and trained subjects. (A) Carbon dioxide partial pressure (pCO2) in arterial blood. (B) Oxygen partial pressure (pO2) in arterial blood. (C) pH in arterial blood. (D) Bicarbonate (HCO3−) in arterial blood. (E) Lactate in arterial blood. (F) Oxygen saturation measured by pulse oximetry. (G) Heart rate (HR). (H) Mean arterial pressure (MAP). (I) Temperature. (J) Score of self-reported symptoms. Data are expressed as mean ± SEM of 12 subjects per group. Gray box indicates period in which the trained subjects practiced their learned breathing techniques. P values between groups were calculated using repeated measures two-way analysis of variance (ANOVA, interaction term). AU, arbitrary units; bpm, beats per minute.

Fig. 2.

Cardiorespiratory and biochemical changes during cyclic hyperventilation and breath retention in a representative subject of the trained group. (A) The respiratory rate alternately increased to around 20 breaths per minute (bpm) for several minutes, and then dropped to zero during voluntary breath retention. These cyclic changes in respiration resulted in profound changes in (B) oxygen saturation, (C) heart rate, and (D) mean arterial pressure. The data depicted were sampled from the monitor every 10 s. At the end of each hyperventilation phase and breath retention phase, an arterial blood sample was drawn for arterial blood gas analysis, of which the results are listed in the table below D. The cycles of hyper/hypoventilation in this particular subject can be viewed in Movie S2.

Fig. 3.

Plasma cathecholamine concentrations and serum cortisol concentrations during experimental endotoxemia in control and trained subjects. (A) Plasma epinephrine. (B) Plasma norepinephrine. (C) Plasma dopamine. (D) Serum cortisol. Data are expressed as mean ± SEM of 12 subjects per group. Gray box indicates period in which the trained subjects practiced their learned breathing techniques. P values between groups were calculated using repeated measures two-way analysis of variance (ANOVA, interaction term).

Fig. 4.

Plasma cytokine concentrations during endotoxemia in control and trained subjects. (A, C, E, and G) Median values of pro- (TNF-α, IL-6, and IL-8) and anti-inflammatory (IL-10) cytokines (n = 12 per group). (B, D, F, and H) Median ± interquartile range of area under curve (AUC) of pro- (TNF-α, IL-6, and IL-8) and anti-inflammatory (IL-10) cytokines (n = 12 per group; unit: ×104 pg/mL·h). P values were calculated using Mann–Whitney u tests.

Fig. 5.

Correlations in trained individuals. (A) Correlation between peak plasma levels of epinephrine (at T = 0 h) and plasma levels of the anti-inflammatory cytokine IL-10 at T = 1 h. (B) Correlation between plasma levels of the anti-inflammatory cytokine IL-10 at T = 1 h and peak plasma levels of the proinflammatory cytokine TNF-α (at T = 1.5 h). (C) Correlation between plasma levels of the anti-inflammatory cytokine IL-10 at T = 1 h and peak plasma levels of the proinflammatory cytokine IL-6 (at T = 2 h). (D) Correlation between plasma levels of the anti-inflammatory cytokine IL-10 at T = 1 h and peak plasma levels of the proinflammatory cytokine IL-8 (at T = 2 h). R and P values were calculated using Spearman correlation.