Chang, M. D. | Search bioRxiv

bioRxiv2026

TREM2 encodes plaque macrophage plasticity to mediate atherosclerosis regression

Cholesterol lowering therapies stabilize atherosclerotic plaque and reduce ischemic events, but the molecular mechanisms governing plaque remodeling or regression remain poorly defined. The lipid sensor TREM2 is a key modulator of plaque-associated foam cell development and was upregulated by plaque macrophages in atherosclerosis regression. We examined macrophage- or monocyte-specific Trem2 deletion during regression in mice and found that TREM2 expression on plaque macrophages, not newly recruited monocytes, was required for plaque regression. Trem2 deletion impeded necrotic core resolution, leading us to interrogate the efferocytic capacity of TREM2+ cells during lipid lowering. An in vitro model of cholesterol-experienced ex-lipid associated macrophages (Ex-LAMs) demonstrated that prior lipid priming enhanced efferocytic ability after unloading lipids and maintained expression of lysosomal and cytoskeletal remodeling genes. Augmented TREM2 signaling through genetic models or agonist treatment accelerated efferocytic ability in vitro and plaque regression in vivo. Thus, we posit that a TREM2-dependent ExLAM programming drives atherosclerosis resolution and facilitates beneficial plaque remodeling through enhanced efferocytosis. Overall, targeting the TREM2 pathway may be a viable strategy for stabilizing atherosclerotic plaques in patients treated with aggressive cholesterol control.

immunology↗

bioRxiv2026

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

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.

immunology↗