Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis

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dc.contributor.authorCaldwell, Blake A.en
dc.contributor.authorIe, Susantien
dc.contributor.authorLucas, Amyen
dc.contributor.authorLi, Liwuen
dc.date.accessioned2025-04-15T14:33:03Zen
dc.date.available2025-04-15T14:33:03Zen
dc.date.issued2025-01-15en
dc.description.abstractSepsis is a leading cause of death worldwide, with most patient mortality stemming from lingering immunosuppression in sepsis survivors. This is due in part to immune dysfunction resulting from monocyte exhaustion, a phenotype of reduced antigen presentation, altered CD14/CD16 inflammatory subtypes, and disrupted cytokine production. Whereas previous research demonstrated improved sepsis survival in Ticam2-/- mice, the contribution of TICAM2 to long-term exhaustion memory remained unknown. Using a cecal slurry injection sepsis model, we monitored the establishment and recovery of monocyte exhaustion in Ticam2-/- mice. After one week of recovery, we profiled bone marrow and splenic reservoir monocytes in Ticam2-/- mice and found that, in contrast to the persistent exhaustion observed in wild-type monocytes, Ticam2-/- monocytes largely resembled healthy controls. To determine the impact of TICAM2 ablation on innate epigenetic memory in sepsis, we measured genome-wide DNA methylation in bone marrow monocytes and found that Ticam2-/- cells exhibit a unique profile of altered methylation at CEBPE binding sites and regulatory features for key immune genes such as Dmkn and Btg1. Bearing human translational relevance, a case study of time course blood samples collected from a sepsis patient presenting with SIRS and a positive qSOFA revealed a similar effect in human monocytes, which steadily transition into an exhausted memory characterized by a CD38high; CX3CR1low; HLA-DRlow state within four days of hospital admittance. Together, our data reveal the chronic preservation of monocyte exhaustion, partially controlled by TICAM2.en
dc.description.versionPublished versionen
dc.format.extent12 page(s)en
dc.format.mimetypeapplication/pdfen
dc.identifierARTN 2059 (Article number)en
dc.identifier.doihttps://doi.org/10.1038/s41598-025-86103-xen
dc.identifier.eissn2045-2322en
dc.identifier.issn2045-2322en
dc.identifier.issue1en
dc.identifier.orcidCaldwell, Blake [0000-0002-4263-4058]en
dc.identifier.orcidLi, Liwu [0000-0001-8870-5299]en
dc.identifier.other10.1038/s41598-025-86103-x (PII)en
dc.identifier.pmid39814939en
dc.identifier.urihttps://hdl.handle.net/10919/125196en
dc.identifier.volume15en
dc.language.isoenen
dc.publisherNature Portfolioen
dc.relation.urihttps://www.ncbi.nlm.nih.gov/pubmed/39814939en
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectTicam2en
dc.subjectSepsisen
dc.subjectMonocyte exhaustionen
dc.subjectInnate immune memoryen
dc.subject.meshMonocytesen
dc.subject.meshAnimalsen
dc.subject.meshMice, Inbred C57BLen
dc.subject.meshMice, Knockouten
dc.subject.meshHumansen
dc.subject.meshMiceen
dc.subject.meshSepsisen
dc.subject.meshDisease Models, Animalen
dc.subject.meshDNA Methylationen
dc.subject.meshMaleen
dc.subject.meshImmune System Exhaustionen
dc.title<i>Ticam2</i> ablation facilitates monocyte exhaustion recovery after sepsisen
dc.title.serialScientific Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.otherArticleen
dc.type.otherJournalen
dcterms.dateAccepted2025-01-08en
pubs.organisational-groupVirginia Techen
pubs.organisational-groupVirginia Tech/Scienceen
pubs.organisational-groupVirginia Tech/Science/Biological Sciencesen
pubs.organisational-groupVirginia Tech/Faculty of Health Sciencesen
pubs.organisational-groupVirginia Tech/All T&R Facultyen
pubs.organisational-groupVirginia Tech/Science/COS T&R Facultyen
pubs.organisational-groupVirginia Tech/Post-docsen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Internal Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Internal Medicine/Pulmonary/Sleep Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/TEACH Membersen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Internal Medicine/Secondary Appointment- Internal Medicineen
pubs.organisational-groupVirginia Tech/VT Carilion School of Medicine/Internal Medicine/Internal Med-Subgroupen

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