Adrenal Gland Macrophage-derived TGF-β Governs Vascular Permeability to Drive Monocyte Recruitment during Stress

Abstract

The adrenal glands are central regulators of systemic stress responses through tightly controlled glucocorticoid production. Yet, the contribution of local immune-vascular interactions to adrenal stress adaptation remains poorly understood. Here, we investigated the role of adrenal gland macrophages in coordinating stress-induced immune remodeling and vascular function. By integrating single-cell RNA sequencing datasets across four distinct stress models, including acute cold exposure, chronic social defeat, chronic inflammation, and systemic Candida albicans infection, we identified a conserved increase in monocyte recruitment to the adrenal gland, accompanied by dynamic macrophage transitions. Comparative transcriptomic and ligand-receptor analyses identified transforming growth factor-{beta} (TGF{beta}) as a dominant macrophage-derived signal targeting adrenal endothelial cells across all stress conditions. Pharmacological blockade of TGF{beta} receptor signaling reduced endothelial activation, vascular permeability, and monocyte infiltration into the adrenal gland following stress, without directly altering resident macrophage numbers. Using genetic fate-mapping and conditional knockout models, we demonstrate that macrophage-derived, but not endothelial-derived, TGF{beta} is required to promote enhanced endothelial adhesion molecule expression, vascular fenestration, permeability, and efficient monocyte recruitment. Loss of macrophage TGF{beta} production also led to exacerbated systemic stress hormone levels. Together, these findings uncover a previously unrecognized macrophage-endothelial axis in the adrenal gland, whereby macrophage-derived TGF{beta} regulates vascular properties to support immune cell recruitment and stress adaptation. This immune-vascular crosstalk provides new mechanistic insights into adrenal homeostasis and suggests potential therapeutic avenues for disorders associated with dysregulated chronic stress.