Novel reprogramming of neutrophils modulates inflammation resolution during atherosclerosis

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dc.contributor.authorGeng, S.en
dc.contributor.authorZhang, Y.en
dc.contributor.authorLee, C.en
dc.contributor.authorLi, L.en
dc.contributor.departmentBiological Sciencesen
dc.date.accessioned2019-04-03T12:47:04Zen
dc.date.available2019-04-03T12:47:04Zen
dc.date.issued2019-02-06en
dc.description.abstractNonresolving inflammation perpetuated by innate leukocytes is involved in the pathogenesis of unstable atherosclerosis. However, the role and regulation of neutrophils related to nonresolving inflammation and atherosclerosis are poorly understood. We report herein that chronic subclinical endotoxemia, a risk factor for atherosclerosis, skewed neutrophils into a nonresolving inflammatory state with elevated levels of inflammatory mediators (Dectin-1, MMP9, and LTB4) and reduced levels of homeostatic mediators (LRRC32, TGF, and FPN). The polarization of neutrophils was due to ROS-mediated activation of oxCAMKII, caused by altered peroxisome homeostasis and reduced lysosome fusion. Application of 4-phenylbutyrate (4-PBA) enhanced peroxisome homeostasis of neutrophils, reduced oxCAMKII, and rebalanced the expression profiles of pro- and anti-inflammatory mediators. Adoptive transfer of neutrophils programmed by subclinical endotoxemia rendered exacerbated atherosclerosis. In contrast, transfer of ex vivo programmed neutrophils by 4-PBA reduced the pathogenesis of atherosclerosis. Our data define novel neutrophil dynamics associated with the progression and regression of atherosclerosis.en
dc.description.notesWe thank the members of the Li laboratory for technical assistance and animal husbandry. We also thank A. Rahtes for careful and critical proofreading of the manuscript. This work was supported by grants from the National Institutes of Health (grant no. R01 HL115835 to L.L).en
dc.description.sponsorshipNational Institutes of Health, NIH: R01 HL115835en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1126/sciadv.aav2309en
dc.identifier.issn23752548en
dc.identifier.issue2en
dc.identifier.othereaav2309en
dc.identifier.pmid30775441en
dc.identifier.urihttp://hdl.handle.net/10919/88812en
dc.identifier.volume5en
dc.language.isoen_USen
dc.publisherAmerican Association for the Advancement of Scienceen
dc.rightsCreative Commons Attribution-NonCommercial 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc/4.0/en
dc.titleNovel reprogramming of neutrophils modulates inflammation resolution during atherosclerosisen
dc.title.serialScience Advancesen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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