| First Author | Caldwell BA | Year | 2025 |
| Journal | Sci Rep | Volume | 15 |
| Issue | 1 | Pages | 2059 |
| PubMed ID | 39814939 | Mgi Jnum | J:361420 |
| Mgi Id | MGI:7854641 | Doi | 10.1038/s41598-025-86103-x |
| Citation | Caldwell BA, et al. (2025) Ticam2 ablation facilitates monocyte exhaustion recovery after sepsis. Sci Rep 15(1):2059 |
| abstractText | 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 CD38(high); CX3CR1(low); HLA-DR(low) state within four days of hospital admittance. Together, our data reveal the chronic preservation of monocyte exhaustion, partially controlled by TICAM2. |
