TY - JOUR
T1 - A common genetic variant in TLR1 enhances human neutrophil priming and impacts length of intensive care stay in pediatric sepsis
AU - Whitmore, Laura C.
AU - Hook, Jessica S.
AU - Philiph, Amanda R.
AU - Hilkin, Brieanna M.
AU - Bing, Xinyu
AU - Ahn, Chul
AU - Wong, Hector R.
AU - Ferguson, Polly J.
AU - Moreland, Jessica G.
N1 - Funding Information:
This work was supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases Grant 1R21 AI109127-01 (to J.G.M.) and National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases Grant 1R01AR059703-01A1 (to P.J.F.). Flow cytometry data were obtained at the Flow Cytometry Facility, a Carver College of Medicine Core Research Facilities/Holden Comprehensive Cancer Center Core Laboratory at the University of Iowa.
Publisher Copyright:
© 2016 by The American Association of Immunologists, Inc.
PY - 2016/2/1
Y1 - 2016/2/1
N2 - 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 in certain disease contexts, including sepsis. As PMN priming by TLR4 agonists is well described, we hypothesized that ligation of TLR2/1 or TLR2/6 would prime PMN. Surprisingly,PMNfrom only a subset of donors were primed in response to the TLR2/1 agonist, Pam3CSK4, although PMN from all donors were primed by the TLR2/6 agonist, FSL-1. Priming responses included generation of intracellular and extracellular reactive oxygen species, MAPK phosphorylation, integrin activation, secondary granule exocytosis, and cytokine secretion. Genotyping studies revealed that PMN responsiveness to Pam3CSK4 was enhanced by a common single-nucleotide polymorphism (SNP) in TLR1 (rs5743618). Notably, PMN from donors with the SNP had higher surface levels of TLR1 and were demonstrated to have enhanced association of TLR1 with the endoplasmic reticulum chaperone gp96. We analyzed TLR1 genotypes in a pediatric sepsis database and found that patients with sepsis or septic shock who had a positive blood culture and were homozygous for the SNP associated with neutrophil priming had prolonged pediatric intensive care unit length of stay. We conclude that this TLR1 SNP leads to excessive PMN priming in response to cell stimulation. Based on our finding that septic children with this SNP had longer pediatric intensive care unit stays, we speculate that this SNP results in hyperinflammation in diseases such as sepsis.
AB - 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 in certain disease contexts, including sepsis. As PMN priming by TLR4 agonists is well described, we hypothesized that ligation of TLR2/1 or TLR2/6 would prime PMN. Surprisingly,PMNfrom only a subset of donors were primed in response to the TLR2/1 agonist, Pam3CSK4, although PMN from all donors were primed by the TLR2/6 agonist, FSL-1. Priming responses included generation of intracellular and extracellular reactive oxygen species, MAPK phosphorylation, integrin activation, secondary granule exocytosis, and cytokine secretion. Genotyping studies revealed that PMN responsiveness to Pam3CSK4 was enhanced by a common single-nucleotide polymorphism (SNP) in TLR1 (rs5743618). Notably, PMN from donors with the SNP had higher surface levels of TLR1 and were demonstrated to have enhanced association of TLR1 with the endoplasmic reticulum chaperone gp96. We analyzed TLR1 genotypes in a pediatric sepsis database and found that patients with sepsis or septic shock who had a positive blood culture and were homozygous for the SNP associated with neutrophil priming had prolonged pediatric intensive care unit length of stay. We conclude that this TLR1 SNP leads to excessive PMN priming in response to cell stimulation. Based on our finding that septic children with this SNP had longer pediatric intensive care unit stays, we speculate that this SNP results in hyperinflammation in diseases such as sepsis.
UR - http://www.scopus.com/inward/record.url?scp=84957705651&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84957705651&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1500856
DO - 10.4049/jimmunol.1500856
M3 - Article
C2 - 26729809
AN - SCOPUS:84957705651
SN - 0022-1767
VL - 196
SP - 1376
EP - 1386
JO - Journal of Immunology
JF - Journal of Immunology
IS - 3
ER -