Rationale The increased mortality and morbidity seen in critically injured patients appears associated with systemic inflammatory response syndrome (SIRS) and immune dysfunction, which ultimately predisposes to infection. Mitochondria released by injury could generate danger molecules, for example, ATP, which in turn would be rapidly scavenged by ectonucleotidases, expressed on regulatory immune cells.
Objective To determine the association between circulating mitochondria, purinergic signalling and immune dysfunction after trauma.
Methods We tested the impact of hepatocyte-derived free mitochondria on blood-derived and lung-derived CD8 T cells in vitro and in experimental mouse models in vivo. In parallel, immune phenotypic analyses were conducted on blood-derived CD8 T cells obtained from trauma patients.
Results Isolated intact mitochondria are functional and generate ATP ex vivo. Extracellular mitochondria perturb CD8+ T cells in co-culture, inducing select features of immune exhaustion in vitro. These effects are modulated by scavenging ATP, modelled by addition of apyrase in vitro. Injection of intact mitochondria into recipient mice markedly upregulates the ectonucleotidase CD39, and other immune checkpoint markers in circulating CD8+ T cells. We note that mice injected with mitochondria, prior to instilling bacteria into the lung, exhibit more severe lung injury, characterised by elevated neutrophil influx and by changes in CD8+ T cell cytotoxic capacity. Importantly, the development of SIRS in injured humans, is likewise associated with disordered purinergic signalling and CD8 T cell dysfunction.
Conclusion These studies in experimental models and in a cohort of trauma patients reveal important associations between extracellular mitochondria, aberrant purinergic signalling and immune dysfunction. These pathogenic factors with immune exhaustion are linked to SIRS and could be targeted therapeutically.
- Bacterial Infection
- Critical Care
- Emergency Medicine
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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MSL and SCR are joint senior authors.
Contributors ST-H, GC, MSL, SCR: acquisition of data, analysis and interpretation of data, drafting of the manuscript. GRL, JH, EC, CL, QZ: acquisition of data. DM, WJ, CJH, LEO: critical revision of the manuscript. ST-H, MSL, SCR: writing of the manuscript. SCR: guarantor. All authors have read the manuscript and approved the final version.
Funding The study was supported by the German Research Foundation (DFG TI-988/1-1 to ST-H), National Institutes of Health (HD-098363, GM-116162, and GM-136429 to WJ, R01 DK108894 and R01 DK124408 to MSL and R21 CA164970 to SCR) and the Department of Defense Award W81XWH-16-0464 (to SCR, CJH and LEO).
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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