Unraveling the immunological roles of serum amyloid A3 in aortic immune cell subsets during atherosclerosis progression

Atherosclerosis is a growing concern in developed nations, necessitating the identification of therapeutic targets for advancing personalized medicine. Serum amyloid A3 (Saa3) has been linked to accelerated plaque progression by affecting cholesterol metabolism and modulation of inflammation. We hypothesize that knocking out Saa3 (Saa3-/-) could mitigate plaque development by regulating aortic immune cell compositions during atherosclerosis progression. Using a murine model, we induced atherosclerosis via a gain-of-function mutant PCSK9-encoding adeno-associated viral vector (AAVmPCSK9) in female wild-type (WT) and Saa3-/- mice. Saa3-/- mice developed smaller plaques than WT mice, and single-cell RNA sequencing revealed significant differences in aortic immune cell populations, particularly among aortic macrophages. Aortic macrophages in atherosclerotic Saa3-/-mice represent an anti-inflammatory and tissue-repairing phenotype and the Trem2hi macrophages, characterized by high Gpnmb, Lpl, and Spp1 expressions, predominated over the typical foamy macrophages in Saa3-/- compared to WT mice. Notably, SAA3 regulates cholesterol metabolism and inflammatory responses in foamy macrophages. Our study highlights Saa3 as a key modulator of aortic immune cells that impact atherosclerosis progression.