DPEP2 suppresses hyperinflammation via metabolic reprogramming of macrophages in sepsis.

Summary

Integrating patient single-cell and bulk transcriptomics with mouse models, the authors identify DPEP2 as a negative regulator of sepsis hyperinflammation. EGR1 represses Dpep2, reducing enzymatic cleavage of LTD4 and shunting eicosanoid flux toward PGE2, amplifying NF-κB signaling; lipid nanoparticle delivery of Dpep2 mRNA to monocytes/macrophages mitigated inflammation, organ injury, and improved survival in septic mice.

Key Findings

• DPEP2 expression is reduced in septic patient monocytes/macrophages and inversely correlates with disease severity and outcomes.
• EGR1 represses Dpep2 transcription, reducing DPEP2-mediated LTD4 cleavage and redirecting eicosanoid metabolism toward PGE2, amplifying NF-κB signaling.
• Macrophage-specific Dpep2 loss exacerbates inflammation and organ injury in septic mice, while LNP-mediated Dpep2 mRNA delivery mitigates injury and improves survival.

Clinical Implications

DPEP2 may serve as a biomarker of hyperinflammation and a therapeutic target; mRNA-based augmentation of DPEP2 or modulation of the LTD4–PGE2 axis could be explored in early-phase trials.

Limitations

• Preclinical mouse models; human interventional data are lacking
• Safety, dosing, and off-target effects of myeloid-targeted LNP mRNA require evaluation

Future Directions

Validate DPEP2 as a prognostic/therapeutic biomarker in prospective cohorts; test DPEP2 augmentation and leukotriene/prostaglandin pathway modulators in phase I/II trials.