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Updated: Dec 30, 2025
Evaluation of a Reliable Biomarker in a Cecal Ligation and Puncture-Induced Mouse Model of Sepsis
Published on: December 9, 2022
A membrane-tethering pepducin derived from formyl peptide receptor 3 shows strong therapeutic effects against sepsis
Ha Young Lee1, Hyung Sik Kim1, Yu Sun Jeong1
1Department of Biological Sciences, Sungkyunkwan University, Suwon, 16419, Republic of Korea.
Abstract:
Formyl peptide receptors (FPRs) are G protein-coupled receptors mainly expressed in inflammatory myeloid cells. Previous reports demonstrated that human neutrophils express only FPR1 and FPR2 but not FPR3. Here, we found that FPR3 is expressed in sepsis patient derived neutrophils and Fpr3 is expressed in the mouse neutrophils. To test the role of Fpr3 in neutrophil activity, we synthesized Fpr3 pepducins and successfully developed an agonistic pepducin that stimulates Fpr3, eliciting calcium increase and chemotactic migration of neutrophils. We also found that administration of an Fpr3 pepducin in an experimental mouse sepsis model significantly increased the survival rate. The pepducin markedly inhibited lung injury, splenocyte apoptosis, and inflammatory cytokine production. Bacterial counts were significantly decreased by the pepducin in septic mice. Based on these results, we suggest that FPR3 can be regarded as a new target to control sepsis, and the newly generated Fpr3-based pepducin can be used for the development of anti-septic agents.
Insights
Formyl peptide receptor 3 (FPR3) is newly found in neutrophils. An FPR3-agonist pepducin improved sepsis survival, reduced organ injury, and decreased bacterial load, suggesting FPR3 as a sepsis therapeutic target.
Area of Science:
- Immunology
- Pharmacology
Background:
- Formyl peptide receptors (FPRs) are key in inflammatory myeloid cell function.
- Human neutrophils were previously thought to express only FPR1 and FPR2, not FPR3.
Purpose of the Study:
- To investigate the expression and role of Formyl peptide receptor 3 (FPR3) in neutrophils.
- To develop and evaluate an FPR3-targeting therapeutic for sepsis.
Main Methods:
- Detected FPR3 expression in neutrophils from sepsis patients and mice.
- Synthesized and characterized Fpr3 pepducins, identifying an agonistic variant.
- Administered the Fpr3 pepducin in a murine model of sepsis.
Main Results:
- FPR3 is expressed in neutrophils from sepsis patients and mice.
- An agonistic Fpr3 pepducin induced neutrophil calcium influx and chemotaxis.
- Fpr3 pepducin treatment significantly enhanced survival in a mouse sepsis model.
- Pepducin administration reduced lung injury, splenocyte apoptosis, and inflammatory cytokine levels, while decreasing bacterial counts.
Conclusions:
- FPR3 is a novel target for sepsis intervention.
- An Fpr3-specific pepducin demonstrates therapeutic potential as an anti-septic agent.
