Development of Exhausted Memory Monocytes and Underlying Mechanisms

Simple item page
dc.contributor.authorPradhan, Kishaen
dc.contributor.authorYi, Ziyueen
dc.contributor.authorGeng, Shuoen
dc.contributor.authorLi, Liwuen
dc.date.accessioned2022-03-22T11:56:26Zen
dc.date.available2022-03-22T11:56:26Zen
dc.date.issued2021-10-28en
dc.description.abstractPathogenic inflammation and immuno-suppression are cardinal features of exhausted monocytes increasingly recognized in septic patients and murine models of sepsis. However, underlying mechanisms responsible for the generation of exhausted monocytes have not been addressed. In this report, we examined the generation of exhausted primary murine monocytes through prolonged and repetitive challenges with high dose bacterial endotoxin lipopolysaccharide (LPS). We demonstrated that repetitive LPS challenges skew monocytes into the classically exhausted Ly6C(hi) population, and deplete the homeostatic non-classical Ly6C(lo) population, reminiscent of monocyte exhaustion in septic patients. scRNAseq analyses confirmed the expansion of Ly6C(hi) monocyte cluster, with elevation of pathogenic inflammatory genes previously observed in human septic patients. Furthermore, we identified CD38 as an inflammatory mediator of exhausted monocytes, associated with a drastic depletion of cellular NAD(+); elevation of ROS; and compromise of mitochondria respiration, representative of septic monocytes. Mechanistically, we revealed that STAT1 is robustly elevated and sustained in LPS-exhausted monocytes, dependent upon the TRAM adaptor of the TLR4 pathway. TRAM deficient monocytes are largely resistant to LPS-mediated exhaustion, and retain the non-classical homeostatic features. Together, our current study addresses an important yet less-examined area of monocyte exhaustion, by providing phenotypic and mechanistic insights regarding the generation of exhausted monocytes.</p>en
dc.description.notesFunding This study is partially supported by the grant from National Institutes of Health R01AI136386.en
dc.description.sponsorshipNational Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01AI136386]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.3389/fimmu.2021.778830en
dc.identifier.issn1664-3224en
dc.identifier.other778830en
dc.identifier.pmid34777396en
dc.identifier.urihttp://hdl.handle.net/10919/109385en
dc.identifier.volume12en
dc.language.isoenen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectmonocyte memoryen
dc.subjectexhaustionen
dc.subjectpathogenic inflammationen
dc.subjectCD38en
dc.subjectTRAMen
dc.titleDevelopment of Exhausted Memory Monocytes and Underlying Mechanismsen
dc.title.serialFrontiers in Immunologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

Files

Original bundle
Now showing 1 - 1 of 1
Thumbnail Image
Name:
fimmu-12-778830.pdf
Size:
3.53 MB
Format:
Adobe Portable Document Format
Description:
Published version
Download

Collections

Scholarly Works, Biological Sciences