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.
Highlights
Despite past extensive studies, atherosclerosis and related cardiovascular complications still remain as the leading cause of morbidity and mortality worldwide
To determine the contribution of TRIF-related adaptor molecule (TRAM) to the development of atherosclerosis, we generated Apoe−/− Tram−/− mice, which were fed with high-fat diet (HFD) for 8 weeks
We demonstrate the reprogramming of resolving monocytes through TRAM deletion, which enabled the reduction of inflammatory mediators and the elevation of resolving antiinflammatory mediators
Summary
Atherosclerosis and related cardiovascular complications still remain as the leading cause of morbidity and mortality worldwide. The key bottleneck is the limited understanding of complex inflammatory processes, during which reprogrammed low-grade inflammatory monocytes persist and contribute to atherosclerosis pathogenesis [1,2,3]. Inflammatory monocytes exhibit elevated CCR2/CCR5/ICAM-1 (murine intermediate Ly6C+; classical Ly6C++ inflammatory monocytes, equivalents of human intermediate CD14+CD16+, classical CD14+CD16– inflammatory monocytes) and are the primary innate cells infiltrating atherosclerotic plaques propagating atherosclerosis [4, 5]. Inflammatory monocytes contribute to the pathogenesis of atherosclerosis through their enhanced recruitment and retention within the atherosclerotic plaques, as well as their compromised ability of cleaning up necrotic cell debris [4, 6,7,8]. Murine Ly6Clo monocytes (human equivalent of CD14lo nonclassical monocytes) may adopt “resolving” features conducive to vascular homeostasis and atherosclerosis regression [9, 10]. Precise mechanisms responsible for monocyte polarization associated with atherosclerosis are still not well understood, hindering translational efforts in resolving monocyte-mediated inflammatory polarization and the treatment of atherosclerosis
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
