Abstract
Immune dysfunction is an important factor driving mortality and adverse outcomes after trauma but remains poorly understood, especially at the cellular level. To deconvolute the trauma-induced immune response, we applied single-cell RNA sequencing to circulating and bone marrow mononuclear cells in injured mice and circulating mononuclear cells in trauma patients. In mice, the greatest changes in gene expression were seen in monocytes across both compartments. After systemic injury, the gene expression pattern of monocytes markedly deviated from steady state with corresponding changes in critical transcription factors, which can be traced back to myeloid progenitors. These changes were largely recapitulated in the human single-cell analysis. We generalized the major changes in human CD14+ monocytes into 6 signatures, which further defined 2 trauma patient subtypes (SG1 vs. SG2) identified in the whole-blood leukocyte transcriptome in the initial 12 hours after injury. Compared with SG2, SG1 patients exhibited delayed recovery, more severe organ dysfunction, and a higher incidence of infection and noninfectious complications. The 2 patient subtypes were also recapitulated in burn and sepsis patients, revealing a shared pattern of immune response across critical illness. Our data will be broadly useful to further explore the immune response to inflammatory diseases and critical illness.
Highlights
Trauma causes an abrupt transition from a healthy state to a state best described as a system-wide physiological crisis
To deconvolute the immune response to trauma, scRNA-Seq was performed on peripheral blood mononuclear cells (PBMCs) isolated from mice subjected to tissue trauma with hemorrhagic shock (T/HS) [6, 7] and their uninjured littermates (2 mice/group) (Figure 1A)
At 6 hours after injury, the peak of systemic inflammation [9], the greatest changes were observed in monocytes represented by an obvious transcriptomic shift in the t-distributed stochastic neighbor embedding (t-SNE) plot (Figure 1B) and the largest number of differentially expressed genes (DEGs) (Supplemental Figure 1, B–E)
Summary
Trauma causes an abrupt transition from a healthy state (i.e., homeostasis) to a state best described as a system-wide physiological crisis. Severe injury is so common among humans that it is the leading cause of death and morbidity in individuals under 54 years old. Insights into the mechanisms leading to immune dysfunction after trauma have lagged behind other diseases associated with a disordered immune response. Transcriptomic analysis of unseparated circulating leukocytes from severely injured humans revealed a “genomic storm” with more than 80% of the leukocyte transcriptome altered during the first 28 days after systemic injury [3]. That study introduced a novel paradigm to describe the immune-inflammatory response to trauma: an early induction of excessive proinflammatory pathways and simultaneous suppression of adaptive immune responses. Cabrera et al demonstrated that differential transcriptomic changes could be identified within whole-blood leukocytes within 2 hours in severely injured patients who subsequently developed multiple organ dysfunction syndrome [4]. Little is known about the cell-specific pathways behind the pathogenic inflammation and immunosuppression that follow trauma
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