Knockout or treatment with an antagonist of formyl peptide receptor 1 protects mice from sepsis by inhibiting inflammation

Background

Sepsis is an infection-related systemic inflammation with high mortality rates. Activation of formyl peptide receptor 1 (FPR1) in immune cells can promote their chemotaxis and inflammatory response, which imbalances immune response during the process of sepsis. FPR1 blockade did diminish systemic inflammatory response during bacterial infection. Accordingly, this study tested the hypothesis that knockout or treatment with an antagonist of FPR1 could protect animals from sepsis-related death.

Methods

Wild-type (WT) or Fpr1 gene knockout (Fpr1^−/−) C57BL/6 mice were subjected to the process of cecal ligation and puncture (CLP) to induce different grades of sepsis. Some WT mice were treated with cinnamoylphenylalanine-(D)leucine-phenylalanine-(D)leucine-phenylalanine (cFLFLF), a FPR1 antagonist. Their survival rate was evaluated, their blood and peritoneal flushing samples were collected at 6 and 24 h after the induction of sepsis for biochemical analyses. We also enrolled 143 sepsis patients, their blood and neutrophil samples were collected for analysis of FPR1 expression by RT-qPCR, and their 28-day survival was recorded.

Results

All mice died by day 6 after high grade sepsis regardless of Fpr1^−/− or cFLFLF treatment. Fpr1 gene knockout or cFLFLF treatment increased the survival rate of mice with a mid-to-low grade of sepsis, accompanied by a significant decrease in the levels of serum and peritoneal inflammatory markers (IL-6, IL-1β and TNF-α). Induction of sepsis increased the percentages of blood neutrophils, and the counts of peritoneal bacterial colony forming units, but decreased body temperature in WT mice, but not in the Fpr1^−/− mice or cFLFLF-treated sepstic mice. Analysis of clinical data indicated that sequential organ failure assessment score and old age were independent risk factors for 28-day mortality.

Conclusion

Fpr1 gene knockout or cFLFLF treatment increased the survival rate of animals with a mid-to-low grade of sepsis, in part by inhibiting abdominal and systemic inflammation during the early period of sepsis. FPR1 protein level in neutrophils was not an independent risk factor of 28-day mortality in sepsis patients.