Department of Biological Sciences and.
Graduate Program of Genetics, Biotechnology and Computational Biology, Virginia Tech, Blacksburg, Virginia, USA.
JCI Insight. 2021 Oct 22;6(20):e149651. doi: 10.1172/jci.insight.149651.
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.
极化的低级别炎症单核细胞促进动脉粥样硬化的发病机制。然而，其潜在机制以及解决有利于动脉粥样硬化消退的单核细胞极化的方法尚不清楚。在本报告中，我们证明了 TRIF 相关衔接分子（TRAM）在体内和体外介导单核细胞极化。TRAM 通过激活 SRC 家族激酶 c-SRC 控制单核细胞极化，这不仅诱导 STAT1/STAT5 调节的炎症介质 CCR2 和 SIRP-α，而且还抑制 PPARγ 调节的解决介质 CD200R。由于 TRAM 缺乏增强的 PPARγ 和 Pex5 促进了过氧化物酶体的稳态和细胞内活性氧的减少，进一步有助于建立一个解决的单核细胞表型。TRAM 缺陷单核细胞通过 CD200R 介导的细胞间通讯将解决表型传播给相邻的单核细胞。在转化水平上，我们表明 TRAM 缺陷小鼠对高脂肪饮食诱导的动脉粥样硬化发病机制具有抗性。我们进一步证明，静脉输注 TRAM 缺陷的解决单核细胞到动脉粥样硬化小鼠中可有效减少动脉粥样硬化的进展。总之，我们的数据表明，靶向 TRAM 可能有助于有效产生有利于动脉粥样硬化治疗的解决单核细胞。
