Cell-free nuclear, but not mitochondrial, DNA concentrations correlate with the early host inflammatory response after severe trauma

Julie A Stortz,Scott C Brakenridge,Frederick A Moore,Steven L Raymond,Zhongkai Wang,Joseph Cuschieri,Ronald V Maier,David C Holden,Philip A Efron,Lyle L Moldawer,Russell B Hawkins

doi:10.1038/s41598-019-50044-z

Julie A Stortz, Scott C Brakenridge + Show 9 more

Open Access

https://doi.org/10.1038/s41598-019-50044-z

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Abstract

Severe blunt trauma is associated with an early ‘genomic storm’ which causes simultaneous up- and down-regulation of host protective immunity. Excessive inflammation can lead to organ injury. In the absence of infection, the inflammatory response is presumably driven by release of endogenous alarmins called danger-associated molecular patterns (DAMPs), which initiate immune responses through pattern-recognition receptors (PRR). Here we examined the relationship between concentrations of cell-free (cf) nuclear DNA (ncDNA) and mitochondrial DNA (mtDNA) within 24 hours post trauma with circulating leukocyte transcriptomics and plasma IL-6 concentrations, as well as the patients’ clinical trajectories. In 104 patients enrolled from two level-1 trauma centers, ncDNA and mtDNA concentrations were increased within 24 hours of severe trauma, but only ncDNA concentrations correlated with leukocyte gene expression and outcomes. Surprisingly, ncDNA, not mtDNA concentrations, were significantly elevated in trauma patients who developed chronic critical illness versus rapid clinical recovery. Plasma IL-6 and leukocyte transcriptomics were better predictors of outcomes than cfDNA levels. Although mtDNA and ncDNA are significantly increased in the immediate post-trauma period, the dramatic inflammatory and gene expression changes seen after severe trauma are only weakly correlated with ncDNA concentrations, and more importantly, mtDNA concentrations are not associated with adverse clinical trajectories.

Highlights

Severe blunt trauma remains a common morbid event throughout the world and is associated with what has been termed an early ‘genomic’ or ‘cytokine’ storm1,2
We test the hypothesis that circulating cell-free DNA (cfDNA), mitochondrial DNA (mtDNA) concentrations, are associated with the exaggerated inflammatory response that leads to organ injury and adverse clinical outcomes
Since mtDNA has been proposed to serve as an endogenous alarmin responsible for the immediate and early inflammatory responses, including cytokine and genomic ‘storms’, we initially looked at univariate correlations between cfDNA concentrations and inflammatory and genomic markers (Table 3)

Summary

Introduction

Severe blunt trauma remains a common morbid event throughout the world and is associated with what has been termed an early ‘genomic’ or ‘cytokine’ storm. Many DAMPs, including cell-free DNA (cfDNA), which is comprised of either nuclear DNA (ncDNA) or mitochondrial DNA (mtDNA), are released in degraded and oxidized forms following traumatic injury as a consequence of cellular death, or in some cases, active secretion. Many DAMPs, including cell-free DNA (cfDNA), which is comprised of either nuclear DNA (ncDNA) or mitochondrial DNA (mtDNA), are released in degraded and oxidized forms following traumatic injury as a consequence of cellular death, or in some cases, active secretion4,5 These endogenous alarmins often act through the same pattern recognition receptors (PRRs) and signaling pathways that are used by the host to recognize microbial products, and this gives strength to the observation that the early inflammatory response to severe blunt trauma and microbial infection have similarities. We dichotomized clinical trajectories based on organ injury and duration of intensive care stay since this trauma population exhibits a low inpatient mortality, but is heterogeneous with respect to outcomes, demonstrating significant variation in time to recovery

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