2. Academic Validation
  3. N-formyl methionine mediates NETosis of neutrophil to promote sepsis-induced cardiomyopathy via the FPR1 pathway

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

  • Int Immunopharmacol. 2025 Sep 26:166:115602. doi: 10.1016/j.intimp.2025.115602.
Sen Chen 1,  Hui Lin 2,  Haodi Gu 3,  Xinrou Yu 4,  Junjie Xiang 3,  Lili Xu 5,  Gang Ye 6,  Yue Shan 7,  Yun Wang 8
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China; Department of Clinical Skills Training Center, Hubei University of Medicine, Shiyan 442000, Hubei, China.
  • 2 Department of Cardiology, The Affiliated Lihuili Hospital of Ningbo University, Ningbo, Zhejiang 315211, China.
  • 3 College of Medicine, Shaoxing University, Shaoxing 312000, Zhejiang, China.
  • 4 Department of Cardiology, Zhuji Affiliated Hospital of Wenzhou Medical University, Shaoxing, China.
  • 5 Medical Research Center, Shaoxing People's Hospital, Shaoxing 312000, China.
  • 6 Department of Pain Treatment, Shaoxing People's Hospital, Shaoxing 312000, China.
  • 7 Department of Anesthesiology, Shaoxing People's Hospital, Shaoxing 312000, China. Electronic address: 3002024141@usx.edu.cn.
  • 8 Department of Anesthesiology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China. Electronic address: wangyun129@ccmu.edu.cn.
PMID: 41014772 DOI: 10.1016/j.intimp.2025.115602
Abstract

Introduction: 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.

Methods and results: 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.

Conclusion: These data reveal the role of fMet-mediated FPR1/HIF-1α activation in promoting SIC through the NETosis, indicating novel therapeutic strategy for SIC.

Keywords

Cardiomyopathy; NETs; Neutrophils; Sepsis; fMet.

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