The emerging field of immunometabolism has its basis in that inflammation is a hallmark of many chronic metabolic disorders. Central to the link between the immune and metabolic systems is the mitochondrion, which has been recognized as the major player in the orchestration of inflammatory pathways and immune cell function. While much attention on immunometabolic regulation has been given to conventional mature immune cells, recent few scattered studies on the relationship between metabolism and hematopoietic stem cells (HSCs) raise a completely different perspective on the immunological/metabolic interface between HSC defects and human diseases. How immunometabolism influences HSC function, and what signaling cascades help drive cell-intrinsic immunometabolic modes in HSCs, has begun to emerge as an area of intense interest. We have employed Fanconi anemia (FA), a genetic bone marrow failure syndrome known to impact the immune system, deregulate mitochondrial metabolism and promote inflammation, to study immunometabolic regulation in hematopoietic stem and progenitor cells (HSPCs). We and others have demonstrated that inflammation in FA HSPCs plays a crucial role in FA pathophysiology. Recently, we have shown that FA HSCs are more dependent on mitochondrial respiration relative to glycolysis in their resting state for energy metabolism. However, the mechanism underpinning the link between inflammation and the altered metabolic program in FA HSCs has not been defined. More recently, we exploited the well-established repopulating defect of FA HSCs to conduct an unbiased in vivo shRNA screen followed by global gene profiling and functional studies, and identified a deregulated FA/Hes1/Ppar?/FAO signaling axis as a potential missing link between inflammation and dysfunctional metabolism in the context of FA HSC defect. These preliminary studies suggest that the FA pathway may constitute a key component of a novel immunometabolism axis connecting inflammation, cellular metabolism and HSC function. We hypothesize that the FA pathway regulates HSC immunometabolism involving a pathway hierarchy in which the FA core signals to Fancd2, which then acts in concert with the transcriptional repressor Hes1 to suppress Pparg expression and consequently FAO in HSC maintenance. To test this, we will first determine whether the FA pathway regulates Pparg expression through Hes1 and assess the requirement for the co-repression of Pparg expression by the FA pathway and Hes1 in the regulation of FAO in inflammation-stressed HSCs. We will then investigate the functional link between dysregulated immunometabolism and inflammation-associated HSC defects.
Immunometabolism is an emerging field of investigation at the interface between cell immunity and metabolism. Recent studies on the relationship between metabolism and blood stem cells raise a whole new perspective on the immunological/metabolic interface between stem cell defects and human diseases. The goal of this project is to define the role of a newly identified immunometabolic regulatory axis as a potential missing link between inflammation and dysregulated metabolism in diseased stem cells.
