Work

N-formyl methionine mediates NETosis of neutrophil to promote sepsis-induced cardiomyopathy via the FPR1 pathway

Year: 2025

Type: article

Abstract: Sepsis-induced cardiomyopathy (SIC) is a rapidly advancing condition associated with a poor prognosis due to the lack of effective treatments. Neutrophil extracellular traps (NETs), however, act as a double-edged sword in the innate immune response during sepsis. N-formyl methionine (fMet) has been documented to induce NETs in inflammatory conditions, yet its clinical significance and biological function in SIC remain unclear. In this study, we investigated whether fMet induces excessive NETs, thereby promoting SIC. Clinically, serum fMet levels were quantified using ELISA, revealing a significant elevation in patients with SIC compared to non-sepsis patients and healthy controls. The fMet levels were positively correlated with the NETs-related markers myeloperoxidase (MPO) and double-stranded DNA (dsDNA) in patients with SIC. Treatment with lipopolysaccharide and fMet increased NET formation in human neutrophils and upregulated the expression of formyl peptide receptor 1 (FPR1) and hypoxia-inducible factor 1-alpha (HIF-1α). Furthermore, bone marrow-derived neutrophils (BMDNs) were isolated from global FPR1 knockout mice, and FPR1 deficiency in BMDNs was found to suppress NETosis. The cecal ligation and puncture (CLP) model was employed to induce SIC in mice and we found knockout of FPR1 improved outcomes in CLP mice, as evidenced by survival benefit, increased cardiac function, attenuated cytokine storm, reduced neutrophil infiltration, improved mitochondrial function and suppressed NETosis, compared with those of wild-type (WT) mice. In addition, treatment with FPR1 inhibitor HCH6–1 improved cardiac outcome and inhibits NETosis in CLP mice. These data reveal the role of fMet-mediated FPR1/HIF-1α activation in promoting SIC through the NETosis, indicating novel therapeutic strategy for SIC. This study identified that N-formyl methionine (fMet) act as a diagnostic marker and a therapeutic target for sepsis-induced cardiomyopathy (SIC). Mechanistically, fMet act as an endogenous agonist of FPR1, which is active in neutrophils from both septic mice and patients, to promote NETosis via FPR1/HIF-1α signaling pathway. • fMet was elevated in patients with SIC and correlated with disease diagnosis. • fMet induces NETosis in neutrophils via the FPR1/HIF-1α pathway. • FPR1 inhibitor HCH6–1 attenuates SIC by inhibiting neutrophil NETosis through the FPR1/HIF-1α pathway.

Source: International Immunopharmacology

DOI: 10.1016/j.intimp.2025.115602