TREM-1 as a potential therapeutic target in neonatal sepsis

Bacterial sepsis in neonates is associated with elevated morbidity and mortality. A role for the pro-inflammatory Triggering Receptor Expressed on Myeloid cells-1 (TREM-1) is suspected in the innate immune response to bacteria, but little is known about its activities in infants. To begin exploring the feasibility of treating neonatal sepsis by blocking leukocyte TREM-1, we compared TREM-1 membrane expression and mRNA in newborns without clinical or microbiological evidence of infection, to that of healthy adults. The functionality of pro-inflammatory reactions in leukocyte TREM-1 of newborns was also evaluated.

Twenty term newborns were enrolled in this study and cord blood samples were collected at birth. For comparison, peripheral blood specimens were collected from 20 healthy adults (control adult, CA). The expression of TREM-1 protein and mRNA in leukocytes was detected with flow cytometry and real-time qPCR, respectively. Whole cord blood was also stimulated by Escherichia coli or blocked by the TREM-1-specific peptide LP17 to identify changes in the secretion of pro-inflammatory cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α, as well as soluble TREM-1 (sTREM-1) using enzyme linked immunosorbent assay (ELISA).

Mean fluorescence intensity (MFI) of TREM-1 on leukocytes of newborns appeared comparable to healthy adults [monocytes: 37.5 ± 6.7 vs. 37.6 ± 8.7; polymorphonuclear cells (PMNs): 32.9 ± 6.6 vs. 33.6 ± 5.8]. However, the percentage of PMNs positive for TREM-1 was lower in newborns than in healthy adults (82.3 ± 7.1 vs. 98.6 ± 4.8; P < 0.01); the percentage of TREM-1-positive CD14-positive monocytes was comparable to that of healthy adults (97.1 ± 8.3 vs. 97.5 ± 7.4). Exposure of cord blood to E. coli resulted in increased secretion of IL-6, IL-8, TNF-α, and sTREM-1. In contrast, the concentrations of IL-6, IL-8, and TNF-α decreased by a minimum of 15% when TREM-1 was blocked by LP17 then exposed to E. coli, versus E. coli alone. In addition, the concentration of sTREM-1 was positively correlated with the levels of TNF-α (r = 0.519, P < 0.05), IL-6 (r = 0.507, P < 0.05), and IL-8 (r = 0.538, P < 0.05).

Healthy newborns exhibit expression of TREM-1 on monocytes similar to that in healthy adults, and most PMNs express TREM-1 at the newborn stage. Detection of sTREM-1 in neonatal peripheral blood should be further investigated as a potential method for the diagnosis of neonatal infection. Finally, blocking the TREM-1 signal transduction pathway may reduce inflammatory responses of neonate leukocytes and thereby provide a new strategy for treatment of neonatal infection.