# Major Traumatic Injury and Exposure to Mitochondrial-Derived Damage-Associated Molecular Patterns Promotes Neutrophil Survival Accompanied by Stabilisation of the Anti-Apoptotic Protein Mcl-1

## TL;DR

Traumatic injury delays neutrophil death by stabilizing Mcl-1, possibly through mitochondrial damage signals.

## Contribution

Identifies mtDAMPs as a novel driver of neutrophil survival post-trauma via Mcl-1 stabilization.

## Key findings

- Neutrophil apoptosis is delayed in trauma patients within minutes to hours post-injury.
- Trauma patient serum and mtDAMPs/mtDNA delay apoptosis and stabilize Mcl-1 in healthy neutrophils.
- mtDAMPs may contribute to immune dysregulation by prolonging dysfunctional neutrophil survival.

## Abstract

Traumatic injury leads to an extension of the half-life of circulating neutrophils. However, how quickly neutrophil apoptosis is delayed post-injury is currently unknown, as are the underlying mechanisms and factors that promote this extension of lifespan. During the ultra-early (≤1 h) and acute (4–12 and 48–72 h) post-injury phases, we collected blood samples from 73 adult trauma patients. Following ex vivo culture, neutrophil apoptosis was measured, alongside caspase-3 activation and expression of the anti-apoptotic protein Mcl-1. To identify factors that may promote neutrophil survival post-trauma, neutrophils from healthy controls (HCs) were cultured with mitochondrial-derived damage-associated molecular patterns (mtDAMPs) or mitochondrial DNA (mtDNA). Accompanied by reduced mitochondrial membrane depolarisation, delayed Mcl-1 turnover, and reduced caspase-3 activation, the ex vivo lifespan of neutrophils from trauma patients was significantly enhanced in a protein synthesis-independent manner within minutes to hours after injury. Neutrophils from HCs exhibited delayed apoptosis when cultured in media supplemented with trauma patient serum, which occurred alongside stabilisation of Mcl-1. Culturing HCs neutrophils with mtDAMPs or mtDNA significantly delayed apoptosis rates, promoted stabilisation of Mcl-1, and reduced caspase-3 activation. The release of mtDAMPs from damaged tissue may drive post-trauma immune dysregulation by promoting the survival of dysfunctional neutrophils.