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
Nicholson, Thomas Macleod, Michael Belli, Antonio Lord, Janet M Hazeldine, Jon
Nicholson, Thomas
Macleod, Michael
Belli, Antonio
Lord, Janet M
Hazeldine, Jon
Affiliation
University of Birmingham; University Hospitals Birmingham NHS Foundation Trust
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Publication date
2025-05-21
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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.
Citation
Nicholson T, Macleod M, Belli A, Lord JM, Hazeldine J. 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. Cells. 2025 May 21;14(10):754. doi: 10.3390/cells14100754.
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Article