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 subsets during atherosclerosis progression. Using a murine model, we induced atherosclerosis via a gain-of-function mutant PCSK9-encoding adeno-associated viral vector (AAVmPCSK9) in wild-type (WT) and Saa3 -/- mice. Single-cell RNA sequencing revealed that Saa3 -/- mice developed smaller plaques than WT mice, with significant differences in aortic immune cell populations, particularly aortic macrophages. Saa3 -/- macrophages, characterized by high Gpnmb , Lpl , and Spp1 expressions, predominated over the typical resident foamy macrophages in WT mice. Saa3 -/- mice also showed enhanced intercellular immune communication and increased signaling interactions, suggesting a shift towards an anti-inflammatory and tissue-repairing phenotype. Our study highlights the potential of Saa3 as a therapeutic target for atherosclerosis.