UCLA

Lipid metabolism of immune cells can be rapidly reprogramed by inflammatory signals in a cell type and signal-specific manner. This reprogramming can have profound influence on host defense against pathogens, anti-cancer immunity, self-tolerance, and pathogenesis of autoimmune diseases. Despite its importance, the molecular mechanisms underlying the crosstalk between lipid metabolic reprogramming and host defense are still poorly understood. In this thesis, I focus on defining the crosstalk between cholesterol metabolic reprogramming and Type I IFN immune response in macrophages, a major immune cell type in the body. In macrophages, Type I IFN mediated anti-pathogen responses can be triggered through sensing of various Pathogen Associated Molecular Patterns (PAMPs). On the other hand, cholesterol is a key component of membranes, and its homeostasis is tightly controlled by balancing synthesis, uptake and efflux to ensure proper immune cell function. Recent studies showed that Type I IFN signals modulates cholesterol biosynthetic activities in macrophages to regulate inflammation and to facilitate host defense. However, how this process is achieved at intracellular level remains unclear. The work presented in this thesis focuses on elucidating mechanisms in which Type I IFN regulates synthesis, modification and efflux programs in macrophages. In Chapter 2, I investigated how Type I IFN reprograms cholesterol metabolism at subcellular level to provide resistance to bacterial toxins. In Chapter 3, I investigated how cholesterol homeostasis can regulate the production of Type I IFN through an adaptor protein known as Stimulator of interferon genes (STING). It is our expectation that these studies will mechanistically advance our understanding of the crosstalk between lipid reprogramming and inflammation.