Single-cell transcriptomics provides insights into the stress-immune interplay and informs disease risk.

Environmental stress contributes to many diseases-including cardiovascular disease, mental illness, and autoimmune disorders-through immune dysregulation. Stress operates through the hypothalamic-pituitary-adrenal and sympathoadrenal axes, leading to peripheral secretion of cortisol and norepinephrine. While these stress hormones can profoundly influence immune function, their mechanistic effects at the cell-type level remain poorly understood. To address this knowledge gap, we employed an ex vivo model investigating the transcriptomic responses of primary peripheral blood mononuclear cells and neutrophils to physiological stress levels (i.e., levels reached during in vivo stress) of cortisol and norepinephrine at single-cell resolution. We identified novel stress-hormone-dependent and cell-type-specific transcriptomic changes, including uniquely regulated genes and inflammation-related signatures within distinct innate (e.g., CD163+ monocytes/macrophages and neutrophils) and other immune cell types. The single-cell-derived signatures effectively distinguished individuals with stress-related diseases in two independent human cohorts. Our findings provide cell-type-level insights into how stress hormones modulate immune function relevant to human health.