Intensity- and time-matched acute interval and continuous endurance exercise similarly induce an anti-inflammatory environment in recreationally active runners: focus on PD-1 expression in Tregs and the IL-6/IL-10 axis.

PURPOSE: Acute exercise elicits a transient anti-inflammatory state during the early recovery period. Since recent studies reported on regimen-specific effects on immune-related humoral factors and cellular subsets, this study compared the effects of intensity- and time-matched acute interval and continuous exercise on peripheral anti-inflammatory cellular and humoral immune parameters with a particular focus on the PD-1 expression in CD4+ regulatory T cells (Tregs). METHODS: Twenty-four recreationally active runners (age: 29.7 ± 4.3 years, BMI: 22.2 ± 2.4, VO2peak: 56.6 ± 6.4 ml × kg-1 × min-1) participated in this crossover RCT. Each subject conducted a moderate continuous (MCE) and a high-intensity interval exercise (HIIE) session in a counterbalanced design. Blood was drawn before, immediately after, and 1 h after exercise. Treg subsets and levels of PD-1 and Foxp3 were assessed by flow cytometry. Serum levels of IL-10 and IL-6 were quantified by ELISA. RESULTS: PD-1 levels on Tregs increased within the recovery period after HIIE (p < .001) and MCE (p <  0.001). Total counts of Tregs (HIIE: p = 0.044; MCE: p = .021), naïve Tregs (HIIE: p  < 0.001; MCE: p  < 0.001), and PD-1+ effector Tregs (eTregs) (HIIE: p = .002) decreased 1 h after exercise. IL-10 increased 1 h after HIIE (p < 0.001) and MCE (p = 0.018), while IL-6 increased immediately after both HIIE (p = 0.031) and MCE (p = 0.021). Correlations between changes in IL-6 and IL-10 (p = 0.017, r = 0.379) and baseline VO2peak and Treg frequency (p = 0.002, r = 0.660) were identified. CONCLUSION: This is the first study that investigates PD-1 expression in circulating Tregs after acute exercise, revealing an increase in PD-1 levels on eTregs during the early recovery period after intensity- and time-matched HIIE and MCE. Future studies are needed to investigate the PD-1 signalosome in eTregs, together with the expression of key effector molecules (i.e., IL-10, TGF-ß, IL-35, CTLA-4) to elucidate PD-1-dependent changes in cellular function. Based on changes in serum cytokines, this study further reveals a regimen-independent establishment of an anti-inflammatory milieu and underpins the role of the IL-6/IL-10 axis.

The effect of exercise on regulatory T cells: A systematic review of human and animal studies with future perspectives and methodological recommendations.

Many of the exercise-related health-promoting effects are attributed to beneficial immunomodulation. The restoration of immune homeostasis is context-dependent, meaning either to increase anti-inflammatory signaling to counteract disease progression of non-communicable (auto)inflammatory diseases or to enhance (local) activity of proinflammatory immune cells to slow down or inhibit cancer progression. Regulatory CD4+ T cells (Tregs) represent the main regulatory component of the adaptive immune system that fine-tunes inflammatory responses, keeps them in check and prevents long-lasting autoimmunity. Because often dysregulated in the context of various diseases, emerging treatment approaches aim to modulate their number or inherent anti-inflammatory and immunosuppressive function in a highly disease-specific way. Exercise represents a non-pharmacologic strategy in disease prevention and rehabilitation and may be an effective treatment with few to no side effects to counteract dysregulation of Tregs. To date, several studies have evaluated the effect of exercise on Treg-related outcomes. This review aims at providing a comprehensive overview on alterations of blood- or tissue-derived Treg counts, proportion and functionality following acute and chronic exercise in humans and animal models. From the 60 reviewed studies, an overall disease-specific beneficial effect of chronic exercise on Treg levels in animal models can be stated, while both acute and chronic effects in human studies are less definite. However, Treg phenotyping is less sufficient in the animal studies compared to human studies. Only a limited number of studies investigated Treg functionality. There is a large heterogeneity concerning study design, human population or animal model, exercise protocol, and Treg outcome measure specification which makes it difficult to compare results and draw clear conclusions. Study results are discussed in the context of current concepts in exercise immunology. Finally, future perspectives and methodological recommendations are provided to promote research in this field.

Neuroimmunological and neuroenergetic aspects in exercise-induced fatigue.

Feelings of fatigue not only occur in chronic and acute disease states, but also during prolonged strenuous exercise as a symptom of exhaustion. The underlying mechanisms of fatigue in diseases seem to rely on neuroinflammatory pathways. These pathways are interesting to understand exerciseinduced fatigue regarding immune system to brain signaling and effects of cerebral cytokines. Activation of the immune system incurs a high-energy cost, also in the brain. In consequence immune cells have high energetic priority over other tissues, such as neurons. A neuronal inactivation and corresponding changes in neurotransmission can also be induced by end products of ATP metabolism and elicit feelings of fatigue in diseases and after intensive and prolonged exercise bouts. Since there are no existing models of exercise-induced fatigue that specifically address interactions between neuroimmunologic mechanisms and neuroenergetics, this article is combining scientific evidence across a broad range of disciplines in order to propose an inflammation- and energy-based model for exercise-induced fatigue.