Efferocytosis-associated Mrc1⁺Gas6⁺ macrophages are linked to abdominal aortic aneurysm progression through...

Abdominal aortic aneurysm (AAA) is a progressive vascular disease characterized by chronic inflammation, extracellular matrix degradation, and aortic wall remodeling, yet effective pharmacological therapies remain lacking and how macrophage state heterogeneity contributes to disease progression and defective inflammation resolution remains incompletely understood.

We combined single-cell RNA sequencing of elastase-induced murine AAA with pathway, cell-cell communication, trajectory, and regulon analyses, and validated key findings in vivo by immunostaining and flow cytometry and in vitro by pharmacologic ERK inhibition, gene-expression analysis, and macrophage efferocytosis assays.

Single-cell transcriptomic analysis identified four macrophage subsets in AAA, comprising Thbs1⁺Spp1⁺ inflammatory macrophages, Mrc1⁺Gas6⁺ efferocytosis-associated macrophages, Cdca8⁺ proliferative macrophages, and Cd36⁺Lpl⁺ lipid-handling macrophages. AAA progression was characterized by expansion of Thbs1⁺Spp1⁺ macrophages and emergence of Cdca8⁺ macrophages, together with relative loss of Mrc1⁺Gas6⁺ and Cd36⁺Lpl⁺ macrophages. Thbs1⁺Spp1⁺ macrophages showed inflammatory, chemotactic, oxidative stress, and metabolic remodeling signatures, whereas Mrc1⁺Gas6⁺ macrophages were enriched for efferocytosis- and homeostasis-associated features but exhibited increased apoptosis-related signals and reduced expression of Mertk, Gas6, and Igf1 during AAA progression. ERK signaling was overactivated in AAA and associated with loss of these effectors and impaired macrophage efferocytosis, whereas ERK inhibition restored Mertk, Gas6, and Igf1 expression and enhanced uptake of apoptotic cells in macrophage-line models. Trajectory and regulon analyses further suggested that inflammatory and efferocytosis-associated macrophages follow distinct state trajectories, with Maf emerging as a candidate regulator of the Mrc1⁺Gas6⁺ program.

AAA is characterized by an imbalance between inflammatory and efferocytosis-associated macrophage states. ERK-associated dysfunction of Mrc1⁺Gas6⁺ macrophages may contribute to defective inflammation resolution and represents a potential therapeutic target in aneurysmal disease.