Resolving monocytes generated through TRAM deletion attenuate atherosclerosis

Polarization of low-grade inflammatory monocytes facilitates the pathogenesis of atherosclerosis. However, underlying mechanisms as well as approaches for resolving monocyte polarization conducive for the regression of atherosclerosis are not well established. In this report, we demonstrate that TRAM mediates monocyte polarization in vivo and in vitro. TRAM controls monocyte polarization through activating SFK, which not only induces STAT1/STAT5-regulated inflammatory mediators CCR2 and SIRPα, but also suppresses PPARγ-regulated resolving mediator CD200R. Enhanced PPARγ and Pex5 due to TRAM deficiency facilitates peroxisome homeostasis and reduction of cellular reactive oxygen species (ROS), further contributing to the establishment of resolving monocyte phenotype. TRAM deficient monocytes can propagate the resolving phenotype to neighboring monocytes through CD200R mediated inter-cellular communication. At the translational level, we show that TRAM deficient mice are resistant to high-fat-diet induced pathogenesis of atherosclerosis. We further document that intravenous transfusion of TRAM deficient resolving monocytes into atherosclerotic mice can potently reduce the progression of atherosclerosis. Together, our data reveal that targeting TRAM may facilitate the effective generation of resolving monocytes conducive for the treatment of atherosclerosis.