Generation of resolving memory neutrophils through pharmacological training with 4-PBA or genetic deletion of TRAM

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dc.contributor.authorLin, RuiCien
dc.contributor.authorYi, Ziyueen
dc.contributor.authorWang, Jingen
dc.contributor.authorGeng, Shuoen
dc.contributor.authorLi, Liwuen
dc.date.accessioned2022-07-07T14:51:06Zen
dc.date.available2022-07-07T14:51:06Zen
dc.date.issued2022-04-13en
dc.description.abstractNeutrophils are the dominant leukocytes in circulation and the first responders to infection and inflammatory cues. While the roles of neutrophils in driving inflammation have been widely recognized, the contribution of neutrophils in facilitating inflammation resolution is under-studied. Here, through single-cell RNA sequencing analysis, we identified a subpopulation of neutrophils exhibiting pro-resolving characteristics with greater Cd200r and Cd86 expression at the resting state. We further discovered that 4-PBA, a peroxisomal stress-reducing agent, can potently train neutrophils into the resolving state with enhanced expression of CD200R, CD86, as well as soluble pro-resolving mediators Resolvin D1 and SerpinB1. Resolving neutrophils trained by 4-PBA manifest enhanced phagocytosis and bacterial-killing functions. Mechanistically, the generation of resolving neutrophils is mediated by the PPAR gamma/LMO4/STAT3 signaling circuit modulated by TLR4 adaptor molecule TRAM. We further demonstrated that genetic deletion of TRAM renders the constitutive expansion of resolving neutrophils, with an enhanced signaling circuitry of PPAR gamma/LMO4/STAT3. These findings may have profound implications for the effective training of resolving neutrophils with therapeutic potential in the treatment of both acute infection as well as chronic inflammatory diseases.en
dc.description.notesThis study is partially supported by the grant from the National Institutes of Health R01AI136386. We thank the members of the Li laboratory for their assistance with animal colonies and technical advice.en
dc.description.sponsorshipNational Institutes of Health [R01AI136386]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s41419-022-04809-6en
dc.identifier.issn2041-4889en
dc.identifier.issue4en
dc.identifier.other345en
dc.identifier.pmid35418110en
dc.identifier.urihttp://hdl.handle.net/10919/111155en
dc.identifier.volume13en
dc.language.isoenen
dc.publisherSpringer Natureen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectinflammationen
dc.subjectreceptoren
dc.subjectinjuryen
dc.subjectcellsen
dc.subjectgammaen
dc.subjectexpressionen
dc.subjectd1en
dc.subjectphenylbutyrateen
dc.subjectresolutionen
dc.subjecttherapyen
dc.titleGeneration of resolving memory neutrophils through pharmacological training with 4-PBA or genetic deletion of TRAMen
dc.title.serialCell Death & Diseaseen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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