Resolving monocytes generated through TRAM deletion attenuate atherosclerosis

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dc.contributor.authorGeng, Shuoen
dc.contributor.authorZhang, Yaoen
dc.contributor.authorYi, Ziyueen
dc.contributor.authorLu, Ranen
dc.contributor.authorLi, Liwuen
dc.date.accessioned2022-03-22T17:08:26Zen
dc.date.available2022-03-22T17:08:26Zen
dc.date.issued2021-10-22en
dc.description.abstractPolarization 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-alpha but also suppresses PPAR gamma-regulated resolving mediator CD200R. Enhanced PPAR gamma 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.en
dc.description.notesWe appreciate the assistance from members of the Li laboratory during this study. This work was supported by NIH grant R01 HL 115835 to LL.en
dc.description.sponsorshipNIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01 HL 115835]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1172/jci.insight.149651en
dc.identifier.eissn2379-3708en
dc.identifier.issue20en
dc.identifier.othere149651en
dc.identifier.pmid34499622en
dc.identifier.urihttp://hdl.handle.net/10919/109409en
dc.identifier.volume6en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.titleResolving monocytes generated through TRAM deletion attenuate atherosclerosisen
dc.title.serialJCI Insighten
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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