Regulating Inflammation Through Exercise-Mediated Trained Immunity or Genetic Manipulation of the Interferon Locus

Abstract Inflammation is a protective early immune response to infection or injury. A balanced inflammatory response, which is self-limiting and self-resolving, is essential to restore homeostasis. However, dysregulated inflammation is underlying many chronic diseases and infections. Strategies for balancing inflammation can be achieved in two ways 1) by inducing adaptations in immune cells through environmental/lifestyle factors such as exercise and 2) by genetically manipulating or pharmaceutically targeting key immune modulatory factors, such as interferons. In my thesis, I employed both approaches. First, we explored whether exercise training could induce adaptations in bone marrow-derived macrophages, resulting in trained immunity, known to occur in immune cells due to persistent metabolic and epigenetic changes. Data from this study suggest that chronic moderate exercise can influence the inflammatory responses of macrophages by reprogramming their metabolic and epigenetic landscape. Second, we evaluated the role of specific type I interferons (IFN-α and IFN-β), cytokines known for their antiviral and immunomodulatory functions, in virus infection and PAMPs (pathogen-associated molecular patterns) mediated inflammatory responses. To study this, we generated unique knockout (KO) mice of type I interferons (IFN-Is) locus and evaluated viral clearance and other parameters such as cytokine, interferon stimulated genes (ISG) signatures, and bone marrow hematopoiesis. Data from this study showed the importance of IFN-αs in early viral clearance and other parameters that measured antiviral and inflammatory responses, which encourages the need to study the individual IFN-Is in isolation using reliable mouse models to uncover their specific roles and targets. Overall, data from both approaches contributed significantly to improving our understanding of the mechanisms behind exercise and IFN-I mediated regulation of inflammatory responses.