Abstract
Polarization of low-grade inflammatory monocytes facilitates the pathogenesis of atherosclerosis. However, underlying mechanisms as well as approaches for resolving monocyte polarization conducive to the regression of atherosclerosis are not well established. In this report, we demonstrate that TRIF-related adaptor molecule (TRAM) mediated monocyte polarization in vivo and in vitro. TRAM controlled monocyte polarization through activating Src family kinase c-SRC, which not only induces STAT1/STAT5-regulated inflammatory mediators CCR2 and SIRP-α but also suppresses PPARγ-regulated resolving mediator CD200R. Enhanced PPARγ and Pex5 due to TRAM deficiency facilitated peroxisome homeostasis and reduction of cellular reactive oxygen species, further contributing to the establishment of a resolving monocyte phenotype. TRAM-deficient monocytes propagated the resolving phenotype to neighboring monocytes through CD200R-mediated intercellular communication. At the translational level, we show that TRAM-deficient mice were resistant to high-fat diet–induced pathogenesis of atherosclerosis. We further document that intravenous transfusion of TRAM-deficient resolving monocytes into atherosclerotic mice potently reduced 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.
Authors
Shuo Geng, Yao Zhang, Ziyue Yi, Ran Lu, Liwu Li
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