Cachexia, or the inflammatory loss of lean body mass, is a leading predictor of morbidity across chronic diseases. A disease of complex etiology, cachexia has proven difficult to model in animals. Little is known regarding the molecular mechanisms controlling cachexia onset, persistence and pathology; and widely efficacious interventions to reverse cachexia are lacking. We have recently shown that Toxoplasma infection in mice is novel animal model to study sustained cachexia. The longevity of this model has led to the discovery that chronically cachectic mice have perivascular fibrosis in the liver. Importantly, we have found that mice defective in the IL-1 innate immune signaling pathway are protected from cachexia and fibrosis and altered lipid metabolism, despite harboring a similar titer of Toxoplasma as WT animals. We hypothesize that cachexia is a cost of long-term IL-1 signaling. In this proposal we will determine whether eliminating chronic infection or blocking fibrosis is sufficient to reverse cachexia. We will identify the IL-1R expressing cell types driving cachexia and determine how IL-1 signaling on fibroblasts and/or endothelial cells control aberrant lipid metabolism in cachectic livers. Our studies are timely, as a recent clinical study demonstrated that blocking human IL-1a with a monoclonal antibody has reversed some symptoms of cachexia. Thus, we have a novel model to understand the mechanism of IL-1 function in cachexia and test therapeutic interventions for disease reversal. Understanding the role of the IL-1 axis in cachexia will improve the life span and comfort of patients suffering from a wide range of debilitating chronic diseases.
Cachexia is a major predictor of mortality that occurs with almost all chronic diseases. This project will identify the mechanism by which IL-1 promotes cachexia pathophysiology, fibrosis and lipid dysregulation. Effective tools to combat cachexia will impact a wide range of patients by: 1) increasing survival of physically taxing treatment; 2) increasing life span so that new therapies can be implemented 3) reduce debilitating pain and fatigue.
