N-formyl methionine mediates NETosis of neutrophil to promote sepsis-induced cardiomyopathy via the FPR1 pathway.
Summary
Serum fMet is elevated in SIC and correlates with NET markers. Genetic deletion or pharmacologic inhibition of FPR1 suppresses NETosis and improves survival and cardiac function in CLP sepsis, positioning the fMet–FPR1/HIF-1α axis and NETosis as actionable targets in SIC.
Key Findings
- Serum fMet was significantly higher in SIC patients and correlated with MPO and dsDNA.
- fMet plus LPS increased NET formation and upregulated FPR1 and HIF-1α in human neutrophils.
- FPR1 knockout suppressed NETosis; in CLP mice, FPR1 deficiency improved survival and cardiac function and reduced inflammation.
- The FPR1 inhibitor HCH6-1 improved cardiac outcomes and reduced NETosis in CLP sepsis.
Clinical Implications
FPR1 inhibitors and monitoring of fMet may guide risk stratification and future therapeutic trials for SIC; NET-modulating strategies warrant translational development.
Why It Matters
This study integrates patient biomarker data with mechanistic in vitro and in vivo evidence, identifying FPR1 as a tractable target to mitigate sepsis-induced cardiomyopathy via NETosis modulation.
Limitations
- Clinical cohort size and setting not detailed; biomarker observations require external validation
- Murine models may not fully recapitulate human SIC; no human interventional data
Future Directions
Validate fMet as a prognostic biomarker and test selective FPR1 inhibitors in large-animal models and early-phase clinical trials for SIC.
Study Information
- Study Type
- Case-control
- Research Domain
- Pathophysiology
- Evidence Level
- V - Preclinical mechanistic evidence from in vitro and animal models with supportive patient biomarker data
- Study Design
- OTHER