Role of the ADAR1-mediated RNA editing ∕ RNA sensing axis in sterile inflammation

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Summary The prevalence of metabolic disease has been steadily increasing, and over two-thirds of US adults suffer from being either overweight or obese. This trend is closely associated with type 2 diabetes mellitus and hypertension, and is a major risk factor for multiple chronic diseases, such as atherosclerosis, fatty liver disease, and certain types of cancers. Studies have found that sterile inflammation plays a critical role during the pathologic development of these metabolic diseases. Metabolic stress causes either mild and chronic inflammation, such as in obese patients, or severe inflammation that may lead to an organ’s functional failure, such as in fatty liver patients. Most fatty liver patients are asymptomatic, however, the occurrence of inflammation converts fatty liver to a severe condition – non-alcoholic steatohepatitis (NASH) – which may lead to cirrhosis and eventually liver failure, (NASH has become the primary cause of liver transplantation in US). In addition, tissue inflammation can further worsen the metabolism in a feedback loop, thereby accelerating the progress of metabolic diseases. Therefore, controlling inflammation may potentially be an effective strategy for treating these patients. However, inflammation is a complicated process regulated by many factors and signaling pathways. The mechanisms that regulate the inflammatory reactions need to be carefully defined before effective therapies can be developed. We recently found that accumulation of lipid in cells suppresses cellular RNA processes through downregulation of the RNA editing enzyme ADAR1. We previously demonstrated that deficiency of ADAR1 activates the cytosolic RNA sensing signaling of the innate immune system, which leads to severe inflammatory tissue injuries. Emerging evidence supports that RNA editing plays a critical role in sterile inflammation. However, the molecular mechanism underlying this regulation has not been defined. In this study, we will take advantage of our extensive experience in RNA editing studies, ready-to-be-used animal models, and the combined expertise of our team members to reveal how cellular RNA activates the cytosolic RNA sensing signaling pathway and how RNA editing regulates the cellular RNA’s immunogenicity. Edited and unedited RNAs will be tested and compared in our unique cell models. We will also determine whether and how the ADAR1- mediated RNA editing/RAN sensing axis plays its critical role in the development of inflammatory tissue injury in metabolic disease. Finally, we will test whether RNA sensing signaling can be used as a new therapeutic target to prevent or attenuate inflammatory tissue injuries in a NASH mouse model.