Mapping the impact of sex hormones on macrophage fates and functions

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Cellular and molecular functions in hormonally-controlled tissues, like the female reproductive tract (FRT) and breast, are coordinately controlled by both the endocrine system and the immune system. Immune cells of the FRT must maintain a microenvironment that simultaneously is permissible to fertilization but resistant to foreign pathogens and infection, resulting in a complex milieu of cell types and states. Cyclic changes in steroid sex hormone levels within the FRT and breast, coupled with heterogenous physical compartments in the FRT that each have distinct chemokine, cellular, and metabolite profiles, necessitate a systems-level approach to evaluating the fates and functions of these cells. Of particular interest in are monocytes and macrophages, both tissue resident and monocyte-derived, due to their diverse functions in homeostatic and pathogenic conditions, and their ability to rapidly adapt to shifting tissue milieus. Despite their importance to health and disease, there is a paucity of studies that have used systems approaches to understand the impact of sex hormones on macrophages. We will specifically address this outstanding knowledge gap by employing a systems biology approach to comprehensively characterize the impact that sex hormones have on macrophage fates and functions. We will first deeply profile how hormones impact the functions and transcriptomes of macrophages as a function of exposure time and dose (Aim 1). We will then use longitudinal single-cell RNAs-sequencing (scRNA-seq) and assay for transposase-accessible chromatin followed by sequencing (scATAC-seq) in order to fully map transcriptional and regulatory impacts of sex hormones on the differentiation of monocytes into macrophages (Aim 2). Taken together, by computationally inferring differentiation trajectories, identifying key regulatory elements that underpin how sex hormones modify macrophage behavior, and assessing cytokine secretion phenotypes, we will build a systems level understanding of the cellular programs that are modified by sex hormones to drive specialized macrophage fates and functions. This research has long-term implications for rationally orchestrating macrophage functions and has practical implications for understanding the diverse roles of macrophages populations in hormonally-controlled tissues.