Programming of Monocyte and Macrophage Populations by Early-Life Glucocorticoid Exposure - PROJECT SUMMARY Exposure such pituitary-adrenal (GC) been GC macrophages to adverse environments early in l ife is associate d with prevalent inflammatory human pathologies as inflammatory bowel disease, obesity, and diabetes, as well as allergies and asthma. The hypothalamic- (HPA) axis is a crucial stress response pathway that regulates the production of glucocorticoids i n response to diverse environmental stressors Notably, dysregulation of the HPA axis and GC levels has strongly correlated with morbidities associated with early-life stress exposure. However, how heightened activity early in life leads to short and potentially long-term functional alterations in monocytes and to promote the development of prevalent human pathologies remains poorly understood. Hence, . the overarching goal of this proposal is to investigate the mechanisms through which two prevalent conditions in children, psychological stress and diet-induced obesity (DIO), reprogram the functions of monocyte and macrophage populations in response to elevated GC levels, leading to short and potentially long-term susceptibility to enhanced inflammatory and metabolic disease progression. In the first aim of this proposal, we will elucidate how GC regulate monocyte populations in the gastrointestinal tract in response to early life exposure to psychological stress. Our preliminary data indicate that GC induced by early-life stress promotes the emergence of an inflammatory subset of enteric glial cells characterized by the expression of Nur transcription factors (TF), which in turn induce intestinal inflammation through the recruitment of TNF- expressing monocytes. We now propose to use genomics and novel mouse genetic tools to uncover how stress- induced GC early in life promote the emergence of inflammatory glia as well as the reprogramming of their chromatin landscape. Moreover, we will establish the mechanisms by which this novel glial cell subset remodels intestinal monocyte populations to promote intestinal inflammation in juvenile and potentially adult organisms. In the second aim of this proposal, we will determine how GC regulate macrophage populations in epididymal white adipose tissue (eWAT) during early-life obesity. Using a single-cell RNA sequencing atlas of early-life DIO that we generated, we identified a novel subset of eWAT macrophages exclusively found in juvenile obese mice. This macrophage subset has a striking GC signaling signature which includes the expression of the TF KLF9 and the growth factor IGF-1, both of which have been associated with increased susceptibility to obesity. We now propose to establish how GC induced during early-life obesity promote the emergence of this novel eWAT macrophage subset as well as the reprogramming of their chromatin landscape. Furthermore, we will establish the mechanisms by which this macrophage subset regulates eWAT function through the secretion of IGF-1. Collectively, these studies will answer the long-standing question of how GC induced by adverse environments early in life promote short and potentially long-term functional alterations to myeloid cell populations in multiple tissues, and reveal new insights into deleterious consequences of chronic exposure to these therapeutic agents.
