Myeloperoxidase-anchored ENO1 mediates neutrophil extracellular trap DNA to enhance Treg differentiation via IFITM2 during sepsis.

Summary

This study reveals that NETs directly program Treg differentiation by anchoring ENO1 (via MPO) on CD4+ T cells and recruiting IFITM2 as a DNA receptor to trigger RAP1B–ERK signaling. ENO1 inhibition reduced NET-driven Treg induction and ameliorated sepsis in mice, defining a targetable pathway for sepsis-induced immunosuppression.

Key Findings

• NETs enhance Treg differentiation via direct interaction with CD4+ T cells.
• MPO anchors ENO1 on T cell membranes, recruiting IFITM2, which senses NET-DNA to activate RAP1B–ERK signaling.
• Pharmacologic ENO1 inhibition attenuates NET-induced Treg differentiation and alleviates sepsis in mice.

Clinical Implications

Targeting ENO1 or IFITM2-mediated signaling could mitigate sepsis-induced immunosuppression and reduce secondary infections; translational development and safety profiling are needed.

Limitations

• Primarily preclinical; human validation of pathway components and clinical endpoints is not detailed.
• Potential off-target effects and timing of intervention during sepsis trajectory remain to be defined.

Future Directions

Validate ENO1/IFITM2 signatures in patient samples, develop selective inhibitors/biologics, and test combinatorial strategies that modulate NETs and Treg balance in early-phase trials.