Epigenomic and transcriptomic analyses reveal differences between low-grade inflammation and severe exhaustion in LPS-challenged murine monocytes

Simple item page
dc.contributor.authorNaler, Lynette B.en
dc.contributor.authorHsieh, Yuan-Pangen
dc.contributor.authorGeng, Shuoen
dc.contributor.authorZhou, Ziruien
dc.contributor.authorLi, Liwuen
dc.contributor.authorLu, Changen
dc.date.accessioned2022-08-03T19:33:52Zen
dc.date.available2022-08-03T19:33:52Zen
dc.date.issued2022-01-28en
dc.description.abstractEmerging studies suggest that monocytes can be trained by bacterial endotoxin to adopt distinct memory states ranging from low-grade inflammation to immune exhaustion. While low-grade inflammation may contribute to the pathogenesis of chronic diseases, exhausted monocytes with pathogenic and immune-suppressive characteristics may underlie the pathogenesis of polymicrobial sepsis including COVID-19. However, detailed processes by which the dynamic adaption of monocytes occur remain poorly understood. Here we exposed murine bone-marrow derived monocytes to chronic lipopolysaccharide (LPS) stimulation at low-dose or high-dose, as well as a PBS control. The cells were profiled for genome-wide H3K27ac modification and gene expression. The gene expression of TRAM-deficient and IRAK-M-deficient monocytes with LPS exposure was also analyzed. We discover that low-grade inflammation preferentially utilizes the TRAM-dependent pathway of TLR4 signaling, and induces the expression of interferon response genes. In contrast, high dose LPS uniquely upregulates exhaustion signatures with metabolic and proliferative pathways. The extensive differences in the epigenomic landscape between low-dose and high-dose conditions suggest the importance of epigenetic regulations in driving differential responses. Our data provide potential targets for future mechanistic or therapeutic studies. Lynette Naler and Yuan-Pang Hsieh et al. evaluate epigenomic and transcriptomic differences in mouse bone marrow-derived macrophages following exposure to high or low doses of LPS. Their results suggest that both low- and high-grade inflammation involve TRAM-dependent pathways.en
dc.description.notesThis work was supported by US National Institutes of Health grants R01EB017235 (C.L.) and R01AI136386 (L.L.), and Virginia Tech ICTAS Center for Engineered Health seed grant (C.L.).en
dc.description.sponsorshipUS National Institutes of Health [R01EB017235, R01AI136386]; Virginia Tech ICTAS Center for Engineered Health seed granten
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s42003-022-03035-2en
dc.identifier.eissn2399-3642en
dc.identifier.issue1en
dc.identifier.other102en
dc.identifier.pmid35091696en
dc.identifier.urihttp://hdl.handle.net/10919/111444en
dc.identifier.volume5en
dc.language.isoenen
dc.publisherNature Portfolioen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectnf-kappa-ben
dc.subjecthistone deacetylase 4en
dc.subjectmacrophage polarizationen
dc.subjectpositive feedbacken
dc.subjectalpha productionen
dc.subjectgene-expressionen
dc.subjectinnate immunityen
dc.subjectc-mycen
dc.subjectlipopolysaccharideen
dc.subjectactivationen
dc.titleEpigenomic and transcriptomic analyses reveal differences between low-grade inflammation and severe exhaustion in LPS-challenged murine monocytesen
dc.title.serialCommunications Biologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
s42003-022-03035-2.pdf
Size:
2.54 MB
Format:
Adobe Portable Document Format
Description:
Published version
Download

Collections

Scholarly Works, Chemical Engineering
Scholarly Works, Biological Sciences