Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis
Abstract Sepsis 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...
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Nature Portfolio
2025-01-01
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| Online Access: | https://doi.org/10.1038/s41598-025-86103-x |
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| author | Blake A. Caldwell Susanti Ie Amy Lucas Liwu Li |
| author_facet | Blake A. Caldwell Susanti Ie Amy Lucas Liwu Li |
| author_sort | Blake A. Caldwell |
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| description | Abstract Sepsis 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. |
| format | Article |
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| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-57acf9c9294f461aaac092fc20522dbf2025-01-19T12:24:38ZengNature PortfolioScientific Reports2045-23222025-01-0115111210.1038/s41598-025-86103-xTicam2 ablation facilitates monocyte exhaustion recovery after sepsisBlake A. Caldwell0Susanti Ie1Amy Lucas2Liwu Li3Department of Biological Sciences, Virginia TechCarillion Roanoke Memorial HospitalCarillion Roanoke Memorial HospitalDepartment of Biological Sciences, Virginia TechAbstract Sepsis 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.https://doi.org/10.1038/s41598-025-86103-xTicam2SepsisMonocyte exhaustionInnate immune memory |
| spellingShingle | Blake A. Caldwell Susanti Ie Amy Lucas Liwu Li Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis Scientific Reports Ticam2 Sepsis Monocyte exhaustion Innate immune memory |
| title | Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis |
| title_full | Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis |
| title_fullStr | Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis |
| title_full_unstemmed | Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis |
| title_short | Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis |
| title_sort | ticam2 ablation facilitates monocyte exhaustion recovery after sepsis |
| topic | Ticam2 Sepsis Monocyte exhaustion Innate immune memory |
| url | https://doi.org/10.1038/s41598-025-86103-x |
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