Project 454616

Excessive or aberrantly controlled inflammation plays a determinantal role in human health during aging and in diseases such as diabetes, cardiovascular disease, and neurodegenerative diseases, sepsis. Therefore, understanding mechanisms by which anti-inflammatory pathways can be stimulated may hold significant promise to treat many aspects of age and inflammation related diseases. Exercise has been shown to be beneficial on several physiological outcomes, including longevity, diabetes, cardiovascular disease, neurodegenerative/neuroinflammatory disease, and protects against sepsis. However, the precise molecular mechanisms that contribute to the benefits of exercise, especially the immunological benefits of exercise, remain poorly defined. Recently, it has been shown that in response to exercise there is a trained immunity response resulting in an increase in circulating levels of itaconate. Itaconate is an important anti-inflammatory metabolite, causing a decrease in proinflammatory cytokine production. However, whether this increase in itaconate is important for the immunological benefits of exercise remains unknown. Therefore, the objective of this project is to determine if itaconate is important for protection from sepsis following exercise. We hypothesize that itaconate is required for the anti-inflammatory effects of exercise and will examine the potential mechanism involved. This work is important as exercise is a currently underutilized therapeutic to combat inflammatory diseases, and understanding the mechanisms of protection could lead to the development of new treatments for sepsis and inflammation which could mimic exercise.