A Common Genetic Variant in TLR1 Enhances Human Neutrophil Priming and Impacts Length of Intensive Care Stay in Pediatric Sepsis

摘要: Polymorphonuclear leukocytes (PMN) achieve an intermediate or primed state of activation following stimulation with certain agonists. Primed PMN have enhanced responsiveness to subsequent stimuli, which can be beneficial in eliminating microbes but may cause host tissue damage disease contexts, including sepsis. As priming by TLR4 agonists is well described, we hypothesized that ligation TLR2/1 TLR2/6 would prime PMN. Surprisingly, from only a subset donors were response the agonist, Pam3CSK4, although all FSL-1. Priming responses included generation intracellular and extracellular reactive oxygen species, MAPK phosphorylation, integrin activation, secondary granule exocytosis, cytokine secretion. Genotyping studies revealed Pam3CSK4 was common single-nucleotide polymorphism (SNP) TLR1 (rs5743618). Notably, SNP had higher surface levels demonstrated association endoplasmic reticulum chaperone gp96. We analyzed genotypes pediatric sepsis database found patients septic shock who positive blood culture homozygous for associated neutrophil prolonged intensive care unit length stay. conclude this leads excessive cell stimulation. Based on our finding children longer stays, speculate results hyperinflammation diseases such as