Exercise as a model to study cell-free DNA in inflammatory signaling in health and disease

Circulating cell-free DNA (cfDNA) is an important marker, which is frequently studied to assess the inflammatory state in patients with sepsis, liver disease and autoimmune disease like systemic lupus erythematosus (SLE). Physical exercise causes acute physiologic alterations including induction of inflammatory signaling processes, immune cell shifts, cytokine release, as well as an increase of cfDNA. However, detailed knowledge on cfDNA release in response to exercise and the involvement in inflammatory signaling is lacking.

We study cfDNA liberation in various exercise settings involving healthy people and patients suffering from SLE (n=34), or non-alcoholic fatty liver disease (NAFLD) (n=40) before and after 12 and 8 weeks of exercise intervention, respectively. Implementation of highly sensitive cfDNA quantification without prior purification allows high throughput monitoring of cfDNA changes during and after acute exercise as well as in response to training interventions. Routine exercise testing implementing step-wise incremental cycling or running ergometry leads to acute elevation of cfDNA concentrations of 5.6- or 15-fold, respectively, in healthy athletes. Patients with active or inactive SLE had higher baseline cfDNA levels. However, preliminary analysis indicates a similar release kinetic and half-life of cfDNA from post-exercise plasma compared to healthy population. Exercise training intervention with patients suffering from NAFLD lead to improvement of disease state, which is not accompanied by reduced cfDNA concentrations. Interestingly, patients with an inflammatory nonalcoholic steatohepatitis (NASH) had higher cfDNA levels then NAFL patients.

To further characterize the physiology of cfDNA release in the different patient cohorts, we study the association of cfDNA with extracellular vesicles, which are considered important mediators of immune reactions. A small but considerable proportion of cfDNA released upon exercise is associated with EVs.

Conclusively, physical exercise provides important models to study the physiology of cfDNA release and to gather knowledge on the role of cfDNA in inflammatory signaling processes.