# Trem1 regulates neutrophil metabolism and recruitment in lung ischemia-reperfusion injury

## TL;DR

This study shows that Trem1 influences neutrophil metabolism and recruitment in lung injury after transplantation, suggesting it could be a target for improving transplant outcomes.

## Contribution

The study identifies Trem1 as a novel regulator of neutrophil metabolism and recruitment in lung ischemia-reperfusion injury.

## Key findings

- Trem1 deficiency reduces neutrophil recruitment, NET formation, and tissue damage in lung IRI.
- Trem1 deletion shifts neutrophil metabolism from oxidative phosphorylation to glycolysis.
- TREM1+ neutrophil abundance correlates with primary graft dysfunction severity in clinical samples.

## Abstract

Primary graft dysfunction (PGD) caused by ischemia-reperfusion injury (IRI) is a major complication after lung transplantation, yet its underlying mechanisms remain unclear. Triggering receptor expressed on myeloid cells 1 (Trem1) is an important mediator of inflammation, but its role in neutrophil function and metabolic reprogramming during lung IRI is not well understood. In this study, we used a murine orthotopic lung transplantation model with cold ischemia and reperfusion, and Trem1 knockout (Trem1−/−) and myeloid-specific Trem1 conditional knockout mice (LysmCreTrem1fl) to explore the role of Trem1 in neutrophil recruitment, neutrophil extracellular trap (NET) formation, and metabolism. Our results show that Trem1 expression increases in both mouse and human lungs after reperfusion and correlates with neutrophil infiltration and lung injury. Trem1 deficiency significantly reduced neutrophil and macrophage recruitment, NET formation, and tissue damage. Multi-omics analysis revealed that Trem1 deletion suppressed oxidative phosphorylation (OXPHOS) and induced a metabolic shift in neutrophils toward glycolysis. In clinical samples, the abundance of TREM1+ neutrophils was correlated with PGD severity and OXPHOS activity. These findings identify Trem1 as a key regulator of neutrophil metabolism and recruitment in lung IRI, and suggest that targeting Trem1 may provide a novel therapeutic strategy to mitigate PGD and improve lung transplant outcomes.

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